• A pilot clinical trial of the cytidine deaminase inhibitor tetrahydrouridine combined with decitabine to target DNMT1 in advanced, chemorefractory pancreatic cancer

      Sohal, Davendra; Krishnamurthi, Smitha; Tohme, Rita; Gu, Xiaorong; Lindner, Daniel; Landowski, Terry H; Pink, John; Radivoyevitch, Tomas; Fada, Sherry; Lee, Zhenghong; et al. (E-CENTURY PUBLISHING CORP, 2020-09-01)
      DNA methyltransferase 1 (DNMT1) is scientifically validated as a molecular target to treat chemo-resistant pancreatic ductal adenocarcinoma (PDAC). Results of clinical studies of the pyrimidine nucleoside analog decitabine to target DNMT1 in PDAC have, however, disappointed. One reason is high expression in PDAC of the enzyme cytidine deaminase (CDA), which catabolizes decitabine within minutes. We therefore added tetrahydrouridine (THU) to inhibit CDA with decitabine. In this pilot clinical trial, patients with advanced chemorefractory PDAC ingested oral THU ~10 mg/kg/day combined with oral decitabine ~0.2 mg/kg/day, for 5 consecutive days, then 2X/week. We treated 13 patients with extensively metastatic chemo-resistant PDAC, including 8 patients (62%) with ascites: all had received ≥ 1 prior therapies including gemcitabine/nab-paclitaxel in 9 (69%) and FOLFIRINOX in 12 (92%). Median time on THU/decitabine treatment was 35 days (range 4-63). The most frequent treatment-attributable adverse event was anemia (n=5). No deaths were attributed to THU/decitabine. Five patients had clinical progressive disease (PD) prior to week 8. Eight patients had week 8 evaluation scans: 1 had stable disease and 7 PD. Median overall survival was 3.1 months. Decitabine systemic exposure is expected to decrease neutrophil counts; however, neutropenia was unexpectedly mild. To identify reasons for limited systemic decitabine effect, we measured plasma CDA enzyme activity in PDAC patients, and found a > 10-fold increase in those with metastatic vs resectable PDAC. We concluded that CDA activity is increased not just locally but also systemically in metastatic PDAC, suggesting a need for even higher CDA-inhibitor doses than used here.
    • Reframing tropical savannization: linking changes in canopy structure to energy balance alterations that impact climate

      Stark, Scott C.; Breshears, David D.; Aragón, Susan; Villegas, Juan Camilo; Law, Darin J.; Smith, Marielle N.; Minor, David M.; Assis, Rafael Leandro; de Almeida, Danilo Robert Alves; de Oliveira, Gabriel; et al. (WILEY, 2020-09-15)
      Tropical ecosystems are undergoing unprecedented rates of degradation from deforestation, fire, and drought disturbances. The collective effects of these disturbances threaten to shift large portions of tropical ecosystems such as Amazon forests into savanna-like structure via tree loss, functional changes, and the emergence of fire (savannization). Changes from forest states to a more open savanna-like structure can affect local microclimates, surface energy fluxes, and biosphere-atmosphere interactions. A predominant type of ecosystem state change is the loss of tree cover and structural complexity in disturbed forest. Although important advances have been made contrasting energy fluxes between historically distinct old-growth forest and savanna systems, the emergence of secondary forests and savanna-like ecosystems necessitates a reframing to consider gradients of tree structure that span forest to savanna-like states at multiple scales. In this Innovative Viewpoint, we draw from the literature on forest-grassland continua to develop a framework to assess the consequences of tropical forest degradation on surface energy fluxes and canopy structure. We illustrate this framework for forest sites with contrasting canopy structure that ranges from simple, open, and savanna-like to complex and closed, representative of tropical wet forest, within two climatically distinct regions in the Amazon. Using a recently developed rapid field assessment approach, we quantify differences in cover, leaf area vertical profiles, surface roughness, albedo, and energy balance partitioning between adjacent sites and compare canopy structure with adjacent old-growth forest; more structurally simple forests displayed lower net radiation. To address forest-atmosphere feedback, we also consider the effects of canopy structure change on susceptibility to additional future disturbance. We illustrate a converse transition-recovery in structure following disturbance-measuring forest canopy structure 10 yr after the imposition of a 5-yr drought in the ground-breaking Seca Floresta experiment. Our approach strategically enables rapid characterization of surface properties relevant to vegetation models following degradation, and advances links between surface properties and canopy structure variables, increasingly available from remote sensing. Concluding, we hypothesize that understanding surface energy balance and microclimate change across degraded tropical forest states not only reveals critical atmospheric forcing, but also critical local-scale feedbacks from forest sensitivity to additional climate-linked disturbance.
    • Global distribution and conservation status of ecologically rare mammal and bird species

      Loiseau, Nicolas; Mouquet, Nicolas; Casajus, Nicolas; Grenié, Matthias; Guéguen, Maya; Maitner, Brian; Mouillot, David; Ostling, Annette; Renaud, Julien; Tucker, Caroline; et al. (NATURE RESEARCH, 2020-10-08)
      Identifying species that are both geographically restricted and functionally distinct, i.e. supporting rare traits and functions, is of prime importance given their risk of extinction and their potential contribution to ecosystem functioning. We use global species distributions and functional traits for birds and mammals to identify the ecologically rare species, understand their characteristics, and identify hotspots. We find that ecologically rare species are disproportionately represented in IUCN threatened categories, insufficiently covered by protected areas, and for some of them sensitive to current and future threats. While they are more abundant overall in countries with a low human development index, some countries with high human development index are also hotspots of ecological rarity, suggesting transboundary responsibility for their conservation. Altogether, these results state that more conservation emphasis should be given to ecological rarity given future environmental conditions and the need to sustain multiple ecosystem processes in the long-term. There are many available ways to rank species for conservation prioritization. Here the authors identify species of mammals and birds that are both spatially restricted and functionally distinct, finding that such species are currently insufficiently protected and disproportionately sensitive to current and future threats.
    • The mode of action of the Protein tyrosine phosphatase 1B inhibitor Ertiprotafib

      Kumar, Ganesan Senthil; Page, Rebecca; Peti, Wolfgang; Univ Arizona, Dept Chem & Biochem (PUBLIC LIBRARY SCIENCE, 2020-10-02)
      Protein tyrosine phosphatase 1B (PTP1B) is a validated therapeutic target for the treatment of diabetes and obesity. Ertiprotafib is a PTP1B inhibitor that reached the clinical trial stage for the treatment of diabetes. Interestingly, Ertiprotafib reduces the melting temperature of PTP1B in differential scanning fluorimetry (DSF) assays, different from most drugs that increase the stability of their target upon binding. No molecular data on how Ertiprotafib functions has been published. Thus, to gain molecular insights into the mode of action of Ertiprotafib, we used biomolecular NMR spectroscopy to characterize the molecular details of the PTP1B:Ertiprotafib interaction. Our results show that Ertiprotafib induces aggregation of PTP1B in a concentration dependent manner. This shows that the insufficient clinical efficacy and adverse effects caused by Ertiprotafib is due to its tendency to cause aggregation of PTP1B.
    • The Rockerverse: Packages and Applications for Containerisation with R

      Nüst, Daniel; Eddelbuettel, Dirk; Bennett, Dom; Cannoodt, Robrecht; Clark, Dav; Daróczi, Gergely; Edmondson, Mark; Fay, Colin; Hughes, Ellis; Kjeldgaard, Lars; et al. (R FOUNDATION STATISTICAL COMPUTING, 2020-09-10)
      The Rocker Project provides widely used Docker images for R across different application scenarios. This article surveys downstream projects that build upon the Rocker Project images and presents the current state of R packages for managing Docker images and controlling containers. These use cases cover diverse topics such as package development, reproducible research, collaborative work, cloud-based data processing, and production deployment of services. The variety of applications demonstrates the power of the Rocker Project specifically and containerisation in general. Across the diverse ways to use containers, we identified common themes: reproducible environments, scalability and efficiency, and portability across clouds. We conclude that the current growth and diversification of use cases is likely to continue its positive impact, but see the need for consolidating the Rockerverse ecosystem of packages, developing common practices for applications, and exploring alternative containerisation software.
    • No evidence of male-biased sexual selection in a snake with conventional Darwinian sex roles

      Levine, Brenna A.; Schuett, Gordon W.; Clark, Rulon W.; Repp, Roger A.; Herrmann, Hans-Werner; Booth, Warren; Univ Arizona, Sch Nat Resources & Environm (ROYAL SOC, 2020-10-07)
      Decades of research on sexual selection have demonstrated that 'conventional' Darwinian sex roles are common in species with anisogamous gametes, with those species often exhibiting male-biased sexual selection. Yet, mating system characteristics such as long-term sperm storage and polyandry have the capacity to disrupt this pattern. Here, these ideas were explored by quantifying sexual selection metrics for the western diamond-backed rattlesnake (Crotalus atrox). A significant standardized sexual selection gradient was not found for males (beta (SS) = 0.588, p = 0.199) or females (beta (SS) = 0.151, p = 0.664), and opportunities for sexual selection (I-s) and selection (I) did not differ between males (I-s = 0.069, I = 0.360) and females (I-s = 0.284, I = 0.424; both p > 0.05). Furthermore, the sexes did not differ in the maximum intensity of precopulatory sexual selection (males: s ' (max) = 0.155, females: s ' (max) = 0.080; p > 0.05). Finally, there was no evidence that male snout-vent length, a trait associated with mating advantage, is a target of sexual selection (p > 0.05). These results suggest a lack of male-biased sexual selection in this population. Mating system characteristics that could erode male-biased sexual selection, despite the presence of conventional Darwinian sex roles, are discussed.
    • The host exosome pathway underpins biogenesis of the human cytomegalovirus virion

      Turner, Declan L; Korneev, Denis V; Purdy, John G; de Marco, Alex; Mathias, Rommel A; Univ Arizona, Dept Immunobiol; Univ Arizona, BIO5 Inst (ELIFE SCIENCES PUBLICATIONS LTD, 2020-09-10)
      Human Cytomegalovirus (HCMV) infects over half the world's population, is a leading cause of congenital birth defects, and poses serious risks for immuno-compromised individuals. To expand the molecular knowledge governing virion maturation, we analysed HCMV virions using proteomics, and identified a significant proportion of host exosome constituents. To validate this acquisition, we characterized exosomes released from uninfected cells, and demonstrated that over 99% of the protein cargo was subsequently incorporated into HCMV virions during infection. This suggested a common membrane origin, and utilization of host exosome machinery for virion assembly and egress. Thus, we selected a panel of exosome proteins for knock down, and confirmed that loss of 7/9 caused significantly less HCMV production. Saliently, we report that VAMP3 is essential for viral trafficking and release of infectious progeny, in various HCMV strains and cell types. Therefore, we establish that the host exosome pathway is intrinsic for HCMV maturation, and reveal new host regulators involved in viral trafficking, virion envelopment, and release. Our findings underpin future investigation of host exosome proteins as important modulators of HCMV replication with antiviral potential.
    • An Early Pandemic Analysis of SARS-CoV-2 Population Structure and Dynamics in Arizona

      Ladner, Jason T; Larsen, Brendan B; Bowers, Jolene R; Hepp, Crystal M; Bolyen, Evan; Folkerts, Megan; Sheridan, Krystal; Pfeiffer, Ashlyn; Yaglom, Hayley; Lemmer, Darrin; et al. (AMER SOC MICROBIOLOGY, 2020-09-04)
      In December of 2019, a novel coronavirus, SARS-CoV-2, emerged in the city of Wuhan, China, causing severe morbidity and mortality. Since then, the virus has swept across the globe, causing millions of confirmed infections and hundreds of thousands of deaths. To better understand the nature of the pandemic and the introduction and spread of the virus in Arizona, we sequenced viral genomes from clinical samples tested at the TGen North Clinical Laboratory, the Arizona Department of Health Services, and those collected as part of community surveillance projects at Arizona State University and the University of Arizona. Phylogenetic analysis of 84 genomes from across Arizona revealed a minimum of 11 distinct introductions inferred to have occurred during February and March. We show that >80% of our sequences descend from strains that were initially circulating widely in Europe but have since dominated the outbreak in the United States. In addition, we show that the first reported case of community transmission in Arizona descended from the Washington state outbreak that was discovered in late February. Notably, none of the observed transmission clusters are epidemiologically linked to the original travel-related case in the state, suggesting successful early isolation and quarantine. Finally, we use molecular clock analyses to demonstrate a lack of identifiable, widespread cryptic transmission in Arizona prior to the middle of February 2020.IMPORTANCE As the COVID-19 pandemic swept across the United States, there was great differential impact on local and regional communities. One of the earliest and hardest hit regions was in New York, while at the same time Arizona (for example) had low incidence. That situation has changed dramatically, with Arizona now having the highest rate of disease increase in the country. Understanding the roots of the pandemic during the initial months is essential as the pandemic continues and reaches new heights. Genomic analysis and phylogenetic modeling of SARS-COV-2 in Arizona can help to reconstruct population composition and predict the earliest undetected introductions. This foundational work represents the basis for future analysis and understanding as the pandemic continues.
    • Direct Imaging Discovery of a Young Brown Dwarf Companion to an A2V Star

      Wagner, Kevin; Apai, Dániel; Kasper, Markus; McClure, Melissa; Robberto, Massimo; Currie, Thayne; Univ Arizona, Steward Observ; Univ Arizona, Lunar & Planetary Lab (IOP PUBLISHING LTD, 2020-10-07)
      We present the discovery and spectroscopy of HIP 75056Ab, a companion directly imaged at a very small separation of 0125 to an A2V star in the Scorpius-Centaurus OB2 association. Our observations utilized Very Large Telescope/Spectro-Polarimetric High-contrast Exoplanet Research Experiment between 2015 and 2019, enabling low-resolution spectroscopy (0.95-1.65 mu m), dual-band imaging (2.1-2.25 mu m), and relative astrometry over a four-year baseline. HIP 75056Ab is consistent with spectral types in the range of M6-L2 andT(eff) similar to 2000-2600 K. A comparison of the companion's brightness to evolutionary tracks suggests a mass of similar to 20-30M(Jup). The astrometric measurements are consistent with an orbital semimajor axis of similar to 15-45 au and an inclination close to face-on (i less than or similar to 35 degrees). In this range of mass and orbital separation, HIP 75056Ab is likely at the low-mass end of the distribution of companions formed via disk instability, although a formation of the companion via core accretion cannot be excluded. The orbital constraints are consistent with the modest eccentricity values predicted by disk instability, a scenario that can be confirmed by further astrometric monitoring. HIP 75056Ab may be utilized as a low-mass atmospheric comparison to older, higher-mass brown dwarfs, and also to young giant planets. Finally, the detection of HIP 75056Ab at 0125 represents a milestone in detecting low-mass companions at separations corresponding to the habitable zones of nearby Sun-like stars.
    • The MOSDEF Survey: Neon as a Probe of ISM Physical Conditions at High Redshift

      Jeong, Moon-Seong; Shapley, Alice E.; Sanders, Ryan L.; Runco, Jordan N.; Topping, Michael W.; Reddy, Naveen A.; Kriek, Mariska; Coil, Alison L.; Mobasher, Bahram; Siana, Brian; et al. (IOP PUBLISHING LTD, 2020-10-08)
      We present results on the properties of neon emission inz similar to 2 star-forming galaxies drawn from the MOSFIRE Deep Evolution Field (MOSDEF) survey. Doubly ionized neon ([Neiii]lambda 3869) is detected at >= 3 sigma in 61 galaxies, representing similar to 25% of the MOSDEF sample with H alpha, H beta, and [Oiii]lambda 5007 detections at similar redshifts. We consider the neon emission-line properties of both individual galaxies with [Neiii]lambda 3869 detections and compositez similar to 2 spectra binned by stellar mass. With no requirement of [Neiii]lambda 3869 detection, the latter provide a more representative picture of neon emission-line properties in the MOSDEF sample. The [Neiii]lambda 3869/[Oii]lambda 3727 ratio (Ne3O2) is anticorrelated with stellar mass inz similar to 2 galaxies, as expected based on the mass-metallicity relation. It is also positively correlated with the [Oiii]lambda 5007/[Oii]lambda 3727 ratio (O32), butz similar to 2 line ratios are offset toward higher Ne3O2 at fixed O32, compared with both local star-forming galaxies and individual H iiregions. Despite the offset toward higher Ne3O2 at fixed O32 atz similar to 2, biases in inferred Ne3O2-based metallicity are small. Accordingly, Ne3O2 may serve as an important metallicity indicator deep into the reionization epoch. Analyzing additional rest-optical line ratios including [Neiii]lambda 3869/[Oiii]lambda 5007 (Ne3O3) and [Oiii]lambda 5007/H beta(O3H beta), we conclude that the nebular emission-line ratios ofz similar to 2 star-forming galaxies suggest a harder ionizing spectrum (lower stellar metallicity, i.e., Fe/H) at fixed gas-phase oxygen abundance, compared to systems atz similar to 0. These new results based on neon lend support to the physical picture painted by oxygen, nitrogen, hydrogen, and sulfur emission of an ionized interstellar medium in high-redshift star-forming galaxies irradiated by chemically young,alpha-enhanced massive stars.
    • The Lyman Continuum Escape Survey: Connecting Time-dependent [O III] and [O II] Line Emission with Lyman Continuum Escape Fraction in Simulations of Galaxy Formation

      Barrow, Kirk S. S.; Robertson, Brant E.; Ellis, Richard S.; Nakajima, Kimihiko; Saxena, Aayush; Stark, Daniel P.; Tang, Mengtao; Univ Arizona, Steward Observ (IOP PUBLISHING LTD, 2020-10-20)
      Escaping Lyman continuum photons from galaxies likely reionized the intergalactic medium at redshiftsz greater than or similar to 6. However, the Lyman continuum is not directly observable at these redshifts and secondary indicators of Lyman continuum escape must be used to estimate the budget of ionizing photons. Observationally, at redshiftsz similar to 2-3 where the Lyman continuum is observationally accessible, surveys have established that many objects that show appreciable Lyman continuum escape fractionsf(esc)also show enhanced [Oiii]/[Oii] (O-32) emission line ratios. Here, we use radiative transfer analyses of cosmological zoom-in simulations of galaxy formation to study the physical connection betweenf(esc)and O-32. Like the observations, we find that the largestf(esc)values occur at elevated O-32 similar to 3-10 and that the combination of highf(esc)and low O(32)is extremely rare. While highf(esc)and O(32)often are observable concurrently, the timescales of the physical origin for the processes are very different. Large O(32)values fluctuate on short (similar to 1 Myr) timescales during the Wolf-Rayet-powered phase after the formation of star clusters, while channels of low absorption are established over tens of megayears by collections of supernovae. We find that while there is no direct causal relation betweenf(esc)and O-32, highf(esc)most often occurs after continuous input from star formation-related feedback events that have corresponding excursions to large O(32)emission. These calculations are in agreement with interpretations of observations that largef(esc)tends to occur when O(32)is large, but large O(32)does not necessarily imply efficient Lyman continuum escape.
    • Deep phenotyping of 34,128 adult patients hospitalised with COVID-19 in an international network study

      Burn, Edward; You, Seng Chan; Sena, Anthony G; Kostka, Kristin; Abedtash, Hamed; Abrahão, Maria Tereza F; Alberga, Amanda; Alghoul, Heba; Alser, Osaid; Alshammari, Thamir M; et al. (NATURE RESEARCH, 2020-10-06)
      Comorbid conditions appear to be common among individuals hospitalised with coronavirus disease 2019 (COVID-19) but estimates of prevalence vary and little is known about the prior medication use of patients. Here, we describe the characteristics of adults hospitalised with COVID-19 and compare them with influenza patients. We include 34,128 (US: 8362, South Korea: 7341, Spain: 18,425) COVID-19 patients, summarising between 4811 and 11,643 unique aggregate characteristics. COVID-19 patients have been majority male in the US and Spain, but predominantly female in South Korea. Age profiles vary across data sources. Compared to 84,585 individuals hospitalised with influenza in 2014-19, COVID-19 patients have more typically been male, younger, and with fewer comorbidities and lower medication use. While protecting groups vulnerable to influenza is likely a useful starting point in the response to COVID-19, strategies will likely need to be broadened to reflect the particular characteristics of individuals being hospitalised with COVID-19. Detailed knowledge of the characteristics of COVID-19 patients helps with public health planning. Here, the authors use routinely-collected data from seven databases in three countries to describe the characteristics of >30,000 patients admitted with COVID-19 and compare them with those admitted for influenza in previous years.
    • FADS genetic and metabolomic analyses identify the ∆5 desaturase (FADS1) step as a critical control point in the formation of biologically important lipids

      Reynolds, Lindsay M; Dutta, Rahul; Seeds, Michael C; Lake, Kirsten N; Hallmark, Brian; Mathias, Rasika A; Howard, Timothy D; Chilton, Floyd H; Univ Arizona, Dept Nutr Sci; Univ Arizona, BIO5 Inst (NATURE RESEARCH, 2020-09-28)
      Humans have undergone intense evolutionary selection to optimize their capacity to generate necessary quantities of long chain (LC-) polyunsaturated fatty acid (PUFA)-containing lipids. To better understand the impact of genetic variation within a locus of three FADS genes (FADS1, FADS2, and FADS3) on a diverse family of lipids, we examined the associations of 247 lipid metabolites (including four major classes of LC-PUFA-containing molecules and signaling molecules) with common and low-frequency genetic variants located within the FADS locus. Genetic variation in the FADS locus was strongly associated (p < 1.2 × 10-8) with 52 LC-PUFA-containing lipids and signaling molecules, including free fatty acids, phospholipids, lyso-phospholipids, and an endocannabinoid. Notably, the majority (80%) of FADS-associated lipids were not significantly associated with genetic variants outside of this FADS locus. These findings highlight the central role genetic variation at the FADS locus plays in regulating levels of physiologically critical LC-PUFA-containing lipids that participate in innate immunity, energy homeostasis, and brain development/function.
    • Cadherin repeat 5 mutation associated with Bt resistance in a field-derived strain of pink bollworm

      Wang, Ling; Ma, Yuemin; Wei, Wei; Wan, Peng; Liu, Kaiyu; Xu, Min; Cong, Shengbo; Wang, Jintao; Xu, Dong; Xiao, Yutao; et al. (NATURE RESEARCH, 2020-10-08)
      Evolution of resistance by pests reduces the benefits of transgenic crops that produce insecticidal proteins from Bacillus thuringiensis (Bt). Here we analyzed resistance to Bt toxin Cry1Ac in a field-derived strain of pink bollworm (Pectinophora gossypiella), a global pest of cotton. We discovered that the r14 allele of the pink bollworm cadherin gene (PgCad1) has a 234-bp insertion in exon 12 encoding a mutant PgCad1 protein that lacks 36 amino acids in cadherin repeat 5 (CR5). A strain homozygous for this allele had 237-fold resistance to Cry1Ac, 1.8-fold cross-resistance to Cry2Ab, and developed from neonate to adult on Bt cotton producing Cry1Ac. Inheritance of resistance to Cry1Ac was recessive and tightly linked with r14. PgCad1 transcript abundance in midgut tissues did not differ between resistant and susceptible larvae. Toxicity of Cry1Ac to transformed insect cells was lower for cells expressing r14 than for cells expressing wild-type PgCad1. Wild-type PgCad1 was transported to the cell membrane, whereas PgCad1 produced by r14 was not. In larval midgut tissue, PgCad1 protein occurred primarily on the brush border membrane only in susceptible larvae. The results imply r14 mediates pink bollworm resistance to Cry1Ac by reduced translation, increased degradation, and/or mislocalization of cadherin.
    • Neutral sphingomyelinase 2 regulates inflammatory responses in monocytes/macrophages induced by TNF-α

      Al-Rashed, Fatema; Ahmad, Zunair; Thomas, Reeby; Melhem, Motasem; Snider, Ashley J; Obeid, Lina M; Al-Mulla, Fahd; Hannun, Yusuf A; Ahmad, Rasheed; Univ Arizona, Coll Agr & Life Sci, Dept Nutr Sci (NATURE RESEARCH, 2020-10-08)
      Obesity is associated with elevated levels of TNF-alpha and proinflammatory CD11c monocytes/macrophages. TNF-alpha mediated dysregulation in the plasticity of monocytes/macrophages is concomitant with pathogenesis of several inflammatory diseases, including metabolic syndrome, but the underlying mechanisms are incompletely understood. Since neutral sphingomyelinase-2 (nSMase2: SMPD3) is a key enzyme for ceramide production involved in inflammation, we investigated whether nSMase2 contributed to the inflammatory changes in the monocytes/macrophages induced by TNF-alpha. In this study, we demonstrate that the disruption of nSMase activity in monocytes/macrophages either by chemical inhibitor GW4869 or small interfering RNA (siRNA) against SMPD3 results in defects in the TNF-alpha mediated expression of CD11c. Furthermore, blockage of nSMase in monocytes/macrophages inhibited the secretion of inflammatory mediators IL-1 beta and MCP-1. In contrast, inhibition of acid SMase (aSMase) activity did not attenuate CD11c expression or secretion of IL-1 beta and MCP-1. TNF-alpha-induced phosphorylation of JNK, p38 and NF-kappa B was also attenuated by the inhibition of nSMase2. Moreover, NF-kB/AP-1 activity was blocked by the inhibition of nSMase2. SMPD3 was elevated in PBMCs from obese individuals and positively corelated with TNF-alpha gene expression. These findings indicate that nSMase2 acts, at least in part, as a master switch in the TNF-alpha mediated inflammatory responses in monocytes/macrophages.
    • Helium-rich Superluminous Supernovae from the Zwicky Transient Facility

      Yan, Lin; Perley, D. A.; Schulze, S.; Lunnan, R.; Sollerman, J.; De, K.; Chen, Z. H.; Fremling, C.; Gal-Yam, A.; Taggart, K.; et al. (IOP PUBLISHING LTD, 2020-10-07)
      Helium is expected to be present in the massive ejecta of some hydrogen-poor superluminous supernovae (SLSN-I). However, until now only one event has been identified with He features in its photospheric spectra (PTF10hgi). We present the discovery of a new He-rich SLSN-I, ZTF19aawfbtg (SN2019hge), atz = 0.0866. This event has more than 10 optical spectra at phases from -41 to +103 days relative to the peak, most of which match well with that of PTF10hgi. Confirmation comes from a near-IR spectrum taken at +34 days, revealing Heifeatures with P-Cygni profiles at 1.083 and 2.058 mu m. Using the optical spectra of PTF10hgi and SN2019hge as templates, we examined 70 other SLSNe-I discovered by Zwicky Transient Facility in the first two years of operation and found five additional SLSNe-I with distinct He-features. The excitation of Heiatoms in normal core-collapse supernovae requires nonthermal radiation, as proposed by previous studies. These He-rich events cannot be explained by the traditional(56)Ni mixing model because of their blue spectra, high peak luminosities, and long rise timescales. Magnetar models offer a possible solution since pulsar winds naturally generate high-energy particles, potential sources of nonthermal excitation. An alternative model is the interaction between the ejecta and dense H-poor circumstellar material, which may be supported by observed undulations in the light curves. These six SLSNe-Ib have relatively low-peak luminosities (rest frameM(g) = -20.06 0.16).
    • A model ensemble generator to explore structural uncertainty in karst systems with unmapped conduits

      Fandel, Chloé; Ferré, Ty; Chen, Zhao; Renard, Philippe; Goldscheider, Nico; Univ Arizona, Dept Hydrol & Atmospher Sci (SPRINGER, 2020-10-02)
      Karst aquifers are characterized by high-conductivity conduits embedded in a low-conductivity fractured matrix, resulting in extreme heterogeneity and variable groundwater flow behavior. The conduit network controls groundwater flow, but is often unmapped, making it difficult to apply numerical models to predict system behavior. This paper presents a multi-model ensemble method to represent structural and conceptual uncertainty inherent in simulation of systems with limited spatial information, and to guide data collection. The study tests the new method by applying it to a well-mapped, geologically complex long-term study site: the Gottesacker alpine karst system (Austria/Germany). The ensemble generation process, linking existing tools, consists of three steps: creating 3D geologic models using GemPy (a Python package), generating multiple conduit networks constrained by the geology using the Stochastic Karst Simulator (a MATLAB script), and, finally, running multiple flow simulations through each network using the Storm Water Management Model (C-based software) to reject nonbehavioral models based on the fit of the simulated spring discharge to the observed discharge. This approach captures a diversity of plausible system configurations and behaviors using minimal initial data. The ensemble can then be used to explore the importance of hydraulic flow parameters, and to guide additional data collection. For the ensemble generated in this study, the network structure was more determinant of flow behavior than the hydraulic parameters, but multiple different structures yielded similar fits to the observed flow behavior. This suggests that while modeling multiple network structures is important, additional types of data are needed to discriminate between networks.
    • Risk Assessment of the Cardiac Pregnant Patient

      Siu, Samuel C; Evans, Kari L; Foley, Michael R; Univ Arizona, Dept Obstet & Gynecol, Coll Med (LIPPINCOTT WILLIAMS & WILKINS, 2020-12)
      Women with heart disease are at increased risk for maternal and fetal complications in pregnancy. Therefore, all women with heart disease should undergo evaluation and counseling, ideally before conception, or as early in pregnancy as possible. In this article we will review the role of risk assessment, the history of development of the cardiac risk prediction tools, and the role of current cardiac risk prediction tools.
    • Pharmacists' perceptions of the pharmacists' patient care process and performance in a simulated patient interaction

      Lott, Breanne E; Anderson, Elizabeth J; Villa Zapata, Lorenzo; Cooley, Janet; Forbes, Stephanie; Taylor, Ann M; Warholak, Terri; Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth; Univ Arizona, Coll Pharm (ELSEVIER, 2020-04-27)
      Objectives: To (1) evaluate the use of the pharmacists' patient care process (PPCP) by licensed pharmacists through a simulated patient activity and (2) describe pharmacists' awareness and perceptions of the PPCP in the state of Arizona. Design: Interviews were conducted to elicit pharmacists' perceptions and awareness of the PPCP. A simulated patient activity involved a role-play pharmacist-patient interaction in a community pharmacy setting. The PPCP was employed as the evaluative framework to assess pharmacist behavior. Setting and participants: Pharmacists licensed in the state of Arizona practicing in various pharmacy settings were recruited through e-mail list serves and snowball recruitment. Data were collected in person, by telephone, and via video chat. Outcome measures: Emergent qualitative themes from interviews were used to describe pharmacists' awareness and perceptions of the PPCP. The presence or absence of PPCP elements were assessed during the simulations. Results: A total of 17 pharmacists were interviewed; 16 participated in the simulated activity. Of these, 7 (41.2%) participants recalled specific details regarding the PPCP process. Participants felt that the PPCP accurately reflected their daily workflow. Accordingly, a mean of 15.8 of the 19 PPCP elements was observed in simulated pharmacist-patient interactions, still allowing room for improvement in pharmacist-led care planning. Participants indicated perceived value in a shared patient care process that facilitates collaboration with myriad health professionals and as an aid to leverage pharmacists' role on health care teams. Conclusion: In this study, pharmacists practicing in Arizona in various settings expressed an awareness of the PPCP, felt it accurately reflected the work they do, and expressed that the tool potentially added value to their work. (C) 2020 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.
    • Extracting Inter-Sentence Relations for Associating Biological Context with Events in Biomedical Texts

      Noriega-Atala, Enrique; Hein, Paul D; Thumsi, Shraddha S; Wong, Zechy; Wang, Xia; Hendryx, Sean M; Morrison, Clayton T; Univ Arizona, Sch Informat; Univ Arizona, Dept Comp Sci; Univ Arizona, Dept Linguist; et al. (IEEE COMPUTER SOC, 2020-12-08)
      We present an analysis of the problem of identifying biological context and associating it with biochemical events described in biomedical texts. This constitutes a non-trivial, inter-sentential relation extraction task. We focus on biological context as descriptions of the species, tissue type, and cell type that are associated with biochemical events. We present a new corpus of open access biomedical texts that have been annotated by biology subject matter experts to highlight context-event relations. Using this corpus, we evaluate several classifiers for context-event association along with a detailed analysis of the impact of a variety of linguistic features on classifier performance. We find that gradient tree boosting performs by far the best, achieving an F1 of 0.865 in a cross-validation study.