Now showing items 2533-2552 of 13152

    • Current Understanding of the Earliest Human Occupations in the Americas: Evaluation of Becerra-Valdivia and Higham (2020)

      Potter, Ben A.; Chatters, James C.; Prentiss, Anna Marie; Fiedel, Stuart J.; Haynes, Gary; Kelly, Robert L.; Kilby, J. David; Lanoë, François; Holland-Lulewicz, Jacob; Miller, D. Shane; et al. (Informa UK Limited, 2021-10-23)
      Various chronologies of the earliest Native American occupations have been proposed with varying levels of empirical support and conceptual rigor, yet none is widely accepted. A recent survey of pre-Clovis dated sites (Becerra-Valdivia and Higham 2020) concludes a pre-Last Glacial Maximum (>26,500–19,000 cal yr BP) entry of humans in the Americas, in part based on recent work at Chiquihuite Cave, Mexico. We evaluate the evidence used to develop this inference. To provide clarity, we present three explicit dispersal models for the earliest human dispersals to the Americas: Strict Clovis-First (13,050 cal yr BP), Paleoindian (<16,000 cal yr BP), and Pre-Paleoindian (>16,000 cal yr BP, encompassing pre-LGM, preferred by Becerra-Valdivia and Higham (2020)), and we summarize the current genetic and archaeological evidence bearing on each. We regard all purported Pre-Paleoindian sites as equivocal and the Strict Clovis-First model to be equally unsupported at present. We conclude that current data strongly support the Paleoindian Dispersal model, with Native American ancestors expanding into the Americas sometime after 16,000 cal yr BP (and perhaps after 14,800 cal yr BP), consistent with well-dated archaeological sites and with genetic data throughout the western hemisphere. Models of the Americas’ peopling that incorporate Chiquihuite or other claimed Pre-Paleoindian sites remain unsubstantiated.
    • Current-conserving relativistic linear response for collisional plasmas

      Formanek, Martin; Grayson, Christopher; Rafelski, Johann; Müller, Berndt; Department of Physics, The University of Arizona (Elsevier BV, 2021-11)
      We investigate the response of a relativistic plasma to electromagnetic fields in the framework of the Boltzmann equation incorporating a collision term in the relaxation rate approximation selected in a form assuring current conservation. We obtain an explicit solution for the linearized perturbation of the Fermi–Dirac equilibrium distribution in terms of the average relaxation rate κ. We study the resulting covariant, gauge invariant, and current conserving form of the polarization tensor in the ultrarelativistic and non-relativistic limits. We evaluate the susceptibility in the ultrarelativistic limit and explore their dependence on κ. Finally, we study the dispersion relations for the longitudinal and transverse poles of the propagator. We show that for κ&gt;2ωp, where ωp is the plasma frequency, the plasma wave modes are overdamped. In the opposite case, κ≪ωp, the propagating plasma modes are weakly damped.
    • Cursed Concepts: New insights on combinatorial processing from ERP correlates of swearing in context

      Donahoo, Stanley A.; Pfeifer, Valeria; Lai, Vicky Tzuyin; Department of Linguistics, University of Arizona; Cognitive Science Program, University of Arizona; Department of Psychology, University of Arizona (Elsevier BV, 2022-03)
      Expressives (damn) convey speaker attitude and when used in context (Tom lost the damn dog) can be flexibly applied locally to the noun (dog) or globally to the whole sentence (the situation). We used ERPs to explore brain responses to expressives in sentences. Participants read expressive, descriptive, and pseudoword adjectives followed by nouns in sentences (The damn/black/flerg dog peed on the couch). At the adjective late-positivity-component (LPC), expressives and descriptives showed no difference, suggesting reduced social threat and that readers employ a ‘wait-and-see’ strategy to interpret expressives. Nouns preceded by expressives elicited a larger frontal P200, as well as reduced N400 and LPC than nouns preceded by descriptives. We associated the frontal P200 with emotional salience, the frontal N400 with mental imagery, and the LPC with cognitive load for combinatorics. We suggest that expressive adjectives are not bound to conceptual integration and conclude that parsers wait-and-see what is being damned.
    • Curved Holographic Waveguide Combiner for HUD and AR Display

      Blanche, Pierre-Alexandre; Draper, Craig T.; Wyant College of Optical Sciences, The University of Arizona (OSA, 2021)
      Waveguide combiners for head up display (HUD) and augmented reality (AR) have the unique advantage to decouple the field of view from the eye box size thanks to pupil replication. However, in order for the image to propagate without aberration in the waveguide, its surfaces have been kept flat and parallel. Here we are presenting a curved waveguide with pupil replication that takes advantage of holographic optical elements for light injection and extraction, while compensating for propagation aberration. Both ray tracing model and early experimental demonstrator are discussed. © OSA 2021.
    • Curved waveguide combiner for HUD/AR

      Blanche, P.-A.; Draper, C.T.; Wyant College of Optical Sciences, University of Arizona (SPIE, 2021)
      Most of waveguide implementation for HUD or augmented reality combiner are flat pieces of glass because the image propagation does not suffer from any aberration when traveling along their length. However, this type of combiner does integrate seamlessly in front of the viewer eyes and a curved optics would be much more appealing. Using holographic optical elements, we demonstrated that it is possible to correct the aberrations induced by the curved surfaces of the waveguide, and display a aberration-free image to the viewer. This correction applies for different waveguide geometries (1D or 2D curvature) as well as different pupil expansions (1D or 2D expansion). A Zemax model is presented along a curved waveguide demonstrator. © COPYRIGHT SPIE. Downloading of the abstract is permitted for personal use only.
    • Cusps enable line attractors for neural computation

      Xiao, Zhuocheng; Zhang, Jiwei; Sornborger, Andrew T.; Tao, Louis; Univ Arizona, Dept Math (AMER PHYSICAL SOC, 2017-11-07)
      Line attractors in neuronal networks have been suggested to be the basis of many brain functions, such as working memory, oculomotor control, head movement, locomotion, and sensory processing. In this paper, we make the connection between line attractors and pulse gating in feed-forward neuronal networks. In this context, because of their neutral stability along a one-dimensional manifold, line attractors are associated with a time-translational invariance that allows graded information to be propagated from one neuronal population to the next. To understand how pulse-gating manifests itself in a high-dimensional, nonlinear, feedforward integrate-and-fire network, we use a Fokker-Planck approach to analyze system dynamics. We make a connection between pulse-gated propagation in the Fokker-Planck and population-averaged mean-field (firing rate) models, and then identify an approximate line attractor in state space as the essential structure underlying graded information propagation. An analysis of the line attractor shows that it consists of three fixed points: a central saddle with an unstable manifold along the line and stable manifolds orthogonal to the line, which is surrounded on either side by stable fixed points. Along the manifold defined by the fixed points, slow dynamics give rise to a ghost. We show that this line attractor arises at a cusp catastrophe, where a fold bifurcation develops as a function of synaptic noise; and that the ghost dynamics near the fold of the cusp underly the robustness of the line attractor. Understanding the dynamical aspects of this cusp catastrophe allows us to show how line attractors can persist in biologically realistic neuronal networks and how the interplay of pulse gating, synaptic coupling, and neuronal stochasticity can be used to enable attracting one-dimensional manifolds and, thus, dynamically control the processing of graded information.
    • Cuspy dark matter density profiles in massive dwarf galaxies

      Cooke, L.H.; Levy, R.C.; Bolatto, A.D.; Simon, J.D.; Newman, A.B.; Teuben, P.; Davey, B.D.; Wright, M.; Tarantino, E.; Lenkić, L.; et al. (Oxford University Press, 2022)
      Rotation curves of galaxies probe their total mass distributions, including dark matter. Dwarf galaxies are excellent systems to investigate the dark matter density distribution, as they tend to have larger fractions of dark matter compared to higher mass systems. The core-cusp problem describes the discrepancy found in the slope of the dark matter density profile in the centres of galaxies (β∗) between observations of dwarf galaxies (shallower cores) and dark matter-only simulations (steeper cusps). We investigate β∗ in six nearby spiral dwarf galaxies for which high-resolution CO J = 1-0 data were obtained with ALMA (Atacama Large Millimeter/submillimeter Array). We derive rotation curves and decompose the mass profile of the dark matter using our CO rotation curves as a tracer of the total potential and 4.5 μm photometry to define the stellar mass distribution. We find β∗= 0.6 with a standard deviation of ±0.1 among the galaxies in this sample, in agreement with previous measurements in this mass range. The galaxies studied are on the high stellar mass end of dwarf galaxies and have cuspier profiles than lower mass dwarfs, in agreement with other observations. When the same definition of the slope is used, we observe steeper slopes than predicted by the FIRE and NIHAO simulations. This may signal that these relatively massive dwarfs underwent stronger gas inflows towards their centres than predicted by these simulations, that these simulations overpredict the frequency of accretion or feedback events, or that a combination of these or other effects are at work. © 2022 The Author(s) Published by Oxford University Press on behalf of Royal Astronomical Society.
    • Cutaneous Metastasis in the Setting of Both Colon and Breast Primary Malignancies

      Junak, Mary; Jecius, Hunter; Erdrich, Jennifer; Univ Arizona, Dept Surg (HINDAWI LTD, 2020-09-29)
      Colorectal cancer (CRC) is the third most diagnosed cancer in the United States, and many patients unfortunately have metastases at the time of their diagnosis. Cutaneous metastases of CRC have been reported in few journals and primarily as case reports due to their rarity. Here, we present the case of an 83-year-old woman with recently resected colon cancer, T4aN1bMx stage IIIB. She presented to our clinic for evaluation of a right midback mass, and a punch biopsy revealed dermal involvement by invasive, poorly differentiated carcinoma with epidermoid features. The mass was excised, and we ordered a PET scan in search of the primary tumor, which at that time was suspected to be of skin cancer origin. Surprisingly, this revealed a second malignancy triple-negative invasive ductal carcinoma of the left breast. The back mass stained positive for CK20, which was compatible with a metastasis from a colonic primary. After initially declining adjuvant therapy, the patient completed one cycle of capecitabine and oxaliplatin, which she tolerated poorly. She continued to further decline, developed widespread cutaneous metastases, and went home on hospice. Cutaneous lesions are an exceedingly rare site of metastasis for colon adenocarcinoma, and their clinical presentation can vary widely. It is important for providers to investigate any new skin lesion in a patient with a recent or remote history of malignancy, even if there were no sites of distant metastasis at initial diagnosis.
    • Cuticular wax variants in a population of switchgrass ( Panicum virgatum L.)

      Weaver, Joshua M.; Lohrey, Greg; Tomasi, Pernell; Dyer, John M.; Jenks, Matthew A.; Feldmann, Kenneth A.; Univ Arizona, Sch Plant Sci (ELSEVIER SCIENCE BV, 2018-07)
      Leaf cuticular waxes are known to influence both biotic and abiotic stress tolerances of plants. The objective of this work was to characterize the wax phenotypic diversity present in a population of 1849 switchgrass plants. We identified 92 visually distinct variant plants that possessed altered leaf glaucousness relative to the common standard type (ST), which exhibited a bluish-white (glaucous) leaf color. The variants could be grouped into three classes: 1) non-glaucous types (NG) that possessed a shiny green leaf surface, 2) reduced glaucous types (RG) that appeared less glaucous than ST, and 3) highly glaucous types (HG) that exhibited more intense bluish white color than ST. Analyses of total cuticular wax content averaged over each of three NG (mean 304.79 +/- 15.16 mu g/dm(2)), RG (mean 533.33 +/- 21.62 mu g/dm(2)) and HG types (mean 1228.23 +/- 45.74 mu g/dm(2)) showed significant differences (P < 0.001) from three selected STs (mean 810.92 +/- 30.57 mu g/dm(2)). Analysis of wax composition among these selected types revealed that the C-33 beta-diketones were the most abundant wax compounds in all but NG types. Field emission scanning electron microscopy showed that abaxial leaf surfaces exhibited predominantly rod-shaped crystals, and adaxial surfaces exhibited predominantly plate-shaped wax crystals on all lines, except for NG that lacked wax crystals on the abaxial leaf surface. As a target for crop improvement, this study reveals that a large amount of variation for cuticle waxes exists within this switchgrass germplasm.
    • Cx43 Channel Gating and Permeation: Multiple Phosphorylation-Dependent Roles of the Carboxyl Terminus

      Ek-Vitorín, José; Pontifex, Tasha; Burt, Janis; Univ Arizona, Dept Physiol (MDPI, 2018-06)
      Connexin 43 (Cx43), a gap junction protein seemingly fit to support cardiac impulse propagation and synchronic contraction, is phosphorylated in normoxia by casein kinase 1 (CK1). However, during cardiac ischemia or pressure overload hypertrophy, this phosphorylation fades, Cx43 abundance decreases at intercalated disks and increases at myocytes' lateral borders, and the risk of arrhythmia rises. Studies in wild-type and transgenic mice indicate that enhanced CK1-phosphorylation of Cx43 protects from arrhythmia, while dephosphorylation precedes arrhythmia vulnerability. The mechanistic bases of these Cx43 (de)phosphoform-linked cardiac phenotypes are unknown. We used patch-clamp and dye injection techniques to study the channel function (gating, permeability) of Cx43 mutants wherein CK1-targeted serines were replaced by aspartate (Cx43-CK1-D) or alanine (Cx43-CK1-A) to emulate phosphorylation and dephosphorylation, respectively. Cx43-CK1-D, but not Cx43-CK1-A, displayed high Voltage-sensitivity and variable permselectivity. Both mutants showed multiple channel open states with overall increased conductivity, resistance to acidification-induced junctional uncoupling, and hemichannel openings in normal external calcium. Modest differences in the mutant channels' function and regulation imply the involvement of dissimilar structural conformations of the interacting domains of Cx43 in electrical and chemical gating that may contribute to the divergent phenotypes of CK1-(de)phospho-mimicking Cx43 transgenic mice and that may bear significance in arrhythmogenesis.
    • Cxcl10 Chemokine Induces Migration of ING4-Deficient Breast Cancer Cells via a Novel Cross Talk Mechanism between the Cxcr3 and Egfr Receptors

      Tsutsumi, Emily; Stricklin, Jeremiah; Peterson, Emily A.; Schroeder, Joyce A.; Kim, Suwon; Clinical Translational Sciences Program, College of Medicine-Phoenix, University of Arizona; Basic Medical Sciences, College of Medicine-Phoenix, University of Arizona (American Society for Microbiology, 2022-02-17)
      The chemokine Cxcl10 has been associated with poor prognosis in breast cancer, but the mechanism is not well understood. Our previous study has shown that CXCL10 was repressed by the ING4 tumor suppressor, suggesting a potential inverse functional relationship. We thus investigated a role for Cxcl10 in the context of ING4 deficiencies in breast cancer. We first analyzed public gene expression data sets and found that patients with CXCL10-high/ING4-low expressing tumors had significantly reduced disease-free survival in breast cancer. In vitro, Cxcl10 induced migration of ING4-deleted breast cancer cells but not of ING4-intact cells. Using inhibitors, we found that Cxcl10-induced migration of ING4-deleted cells required Cxcr3, Egfr, and the Gβγ subunits downstream of Cxcr3 but not Gαi. Immunofluorescent imaging showed that Cxcl10 induced early transient colocalization between Cxcr3 and Egfr in both ING4-intact and ING4-deleted cells, which recurred only in ING4-deleted cells. A peptide agent that binds to the internal juxtamembrane domain of Egfr inhibited Cxcr3/Egfr colocalization and cell migration. Taken together, these results presented a novel mechanism of Cxcl10 that elicits migration of ING4-deleted cells, in part by inducing a physical or proximal association between Cxcr3 and Egfr and signaling downstream via Gβγ. These results further indicated that ING4 plays a critical role in the regulation of Cxcl10 signaling that enables breast cancer progression.
    • CXCR6 by increasing retention of memory CD8 + T cells in the ovarian tumor microenvironment promotes immunosurveillance and control of ovarian cancer

      Muthuswamy, R.; McGray, A.J.R.; Battaglia, S.; He, W.; Miliotto, A.; Eppolito, C.; Matsuzaki, J.; Takemasa, T.; Koya, R.; Chodon, T.; et al. (BMJ Publishing Group, 2021)
      Purpose Resident memory CD8 T cells, owing to their ability to reside and persist in peripheral tissues, impart adaptive sentinel activity and amplify local immune response, and have beneficial implications for tumor surveillance and control. The current study aimed to clarify the less known chemotactic mechanisms that govern the localization, retention, and residency of memory CD8 T cells in the ovarian tumor microenvironment. Experimental design RNA and protein expressions of chemokine receptors in CD8 + resident memory T cells in human ovarian tumor-infiltrating CD8 + T cells and their association with survival were analyzed. The role of CXCR6 on antitumor T cells was investigated using prophylactic vaccine models in murine ovarian cancer. Results Chemokine receptor profiling of CD8 + CD103 + resident memory tumor-infiltrating lymphocytes in patients with ovarian cancer revealed high expression of CXCR6. Analysis of The Cancer Genome Atlas (TCGA) (ovarian cancer database revealed CXCR6 to be associated with CD103 and increased patient survival. Functional studies in mouse models of ovarian cancer revealed that CXCR6 is a marker of resident, but not circulatory, tumor-specific memory CD8 + T cells. CXCR6-deficient tumor-specific CD8 + T cells showed reduced retention in tumor tissues, leading to diminished resident memory responses and poor control of ovarian cancer. Conclusions CXCR6, by promoting retention in tumor tissues, serves a critical role in resident memory T cell-mediated immunosurveillance and control of ovarian cancer. Future studies warrant exploiting CXCR6 to promote resident memory responses in cancers. © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.
    • Cycles of external dependency drive evolution of avian carotenoid networks

      Badyaev, Alexander V; Posner, Alexander B; Morrison, Erin S; Higginson, Dawn M; Univ Arizona, Dept Ecol & Evolutionary Biol (NATURE PUBLISHING GROUP, 2019-04-08)
      All organisms depend on input of exogenous compounds that cannot be internally produced. Gain and loss of such dependencies structure ecological communities and drive species' evolution, yet the evolution of mechanisms that accommodate these variable dependencies remain elusive. Here, we show that historical cycles of gains and losses of external dependencies in avian carotenoid-producing networks are linked to their evolutionary diversification. This occurs because internalization of metabolic controls-produced when gains in redundancy of dietary inputs coincide with increased branching of their derived products-enables rapid and sustainable exploration of an existing network by shielding it from environmental fluctuations in inputs. Correspondingly, loss of internal controls constrains evolution to the rate of the gains and losses of dietary precursors. Because internalization of a network's controls necessarily bridges diet-specific enzymatic modules within a network, it structurally links local adaptation and continuous evolution even for traits fully dependent on contingent external inputs.
    • Cyclic biphalin analogues with a novel linker lead to potent agonist activities at mu, delta, and kappa opioid receptors

      Remesic, Michael; Macedonio, Giorgia; Mollica, Adriano; Porreca, Frank; Hruby, Victor; Lee, Yeon Sun; Univ Arizona, Dept Chem & Biochem; Univ Arizona, Dept Pharmacol (PERGAMON-ELSEVIER SCIENCE LTD, 2018-07-23)
      In an effort to improve biphalin's potency and efficacy at the mu-( MOR) and delta-opioid receptors (DOR), a series of cyclic biphalin analogues 1-5 with a cystamine or piperazine linker at the C-terminus were designed and synthesized by solution phase synthesis using Boc-chemistry. Interestingly, all of the analogues showed balanced opioid agonist activities at all opioid receptor subtypes due to enhanced.-opioid receptor (KOR) activity. Our results indicate that C-terminal flexible linkers play an important role in KOR activity compared to that of the other cyclic biphalin analogues with a hydrazine linker. Among them, analogue 5 is a potent (Ki= 0.27, 0.46, and 0.87 nM; EC50= 3.47, 1.45, and 13.5 nM at MOR, DOR, and KOR, respectively) opioid agonist with high efficacy. Based on the high potency and efficacy at the three opioid receptor subtypes, the ligand is expected to have a potential synergistic effect on relieving pain and further studies including in vivo tests are worthwhile.
    • Cyclic Opioid Peptides.

      Remesic, Michael; Lee, Yeon Sun; Hruby, Victor J; University of Arizona, Department of Chemistry and Biochemistry (BENTHAM SCIENCE PUBL LTD, 2016)
      For decades the opioid receptors have been an attractive therapeutic target for the treatment of pain. Since the first discovery of enkephalin, approximately a dozen endogenous opioid peptides have been known to produce opioid activity and analgesia, but their therapeutics have been limited mainly due to low blood brain barrier penetration and poor resistance to proteolytic degradation. One versatile approach to overcome these drawbacks is the cyclization of linear peptides to cyclic peptides with constrained topographical structure. Compared to their linear parents, cyclic analogs exhibit better metabolic stability, lower offtarget toxicity, and improved bioavailability. Extensive structure-activity relationship studies have uncovered promising compounds for the treatment of pain as well as further elucidate structural elements required for selective opioid receptor activity. The benefits that come with employing cyclization can be further enhanced through the generation of polycyclic derivatives. Opioid ligands generally have a short peptide chain and thus the realm of polycyclic peptides has yet to be explored. In this review, a brief history of designing ligands for the opioid receptors, including classic linear and cyclic ligands, is discussed along with recent approaches and successes of cyclic peptide ligands for the receptors. Various scaffolds and approaches to improve bioavailability are elaborated and concluded with a discourse towards polycyclic peptides.
    • Cyclic strain upregulates VEGF and attenuates proliferation of vascular smooth muscle cells

      Schad, Joseph; Meltzer, Kate; Hicks, Michael; Beutler, David; Cao, Thanh; Standley, Paul; Department of Basic Medical Sciences, University of Arizona - Phoenix, AZ, USA; Department of Biomedical Sciences, Midwestern University - Glendale, AZ, USA; Department of Molecular and Cell Biology, Arizona State University - Tempe, AZ, USA (BioMed Central, 2011)
      OBJECTIVE:Vascular smooth muscle cell (VSMC) hypertrophy and proliferation occur in response to strain-induced local and systemic inflammatory cytokines and growth factors which may contribute to hypertension, atherosclerosis, and restenosis. We hypothesize VSMC strain, modeling normotensive arterial pressure waveforms in vitro, results in attenuated proliferative and increased hypertrophic responses 48 hrs post-strain.METHODS:Using Flexcell Bioflex Systems we determined the morphological, hyperplastic and hypertrophic responses of non-strained and biomechanically strained cultured rat A7R5 VSMC. We measured secretion of nitric oxide, key cytokine/growth factors and intracellular mediators involved in VSMC proliferation via fluorescence spectroscopy and protein microarrays. We also investigated the potential roles of VEGF on VSMC strain-induced proliferation.RESULTS:Protein microarrays revealed significant increases in VEGF secretion in response to 18 hours mechanical strain, a result that ELISA data corroborated. Apoptosis-inducing nitric oxide (NO) levels also increased 43% 48 hrs post-strain. Non-strained cells incubated with exogenous VEGF did not reproduce the antimitogenic effect. However, anti-VEGF reversed the antimitogenic effect of mechanical strain. Antibody microarrays of strained VSMC lysates revealed MEK1, MEK2, phospo-MEK1T385, T291, T298, phospho-Erk1/2T202+Y204/T185+T187, and PKC isoforms expression were universally increased, suggesting a proliferative/inflammatory signaling state. Conversely, VSMC strain decreased expression levels of Cdk1, Cdk2, Cdk4, and Cdk6 by 25-50% suggesting a partially inhibited proliferative signaling cascade.CONCLUSIONS:Subjecting VSMC to cyclic biomechanical strain in vitro promotes cell hypertrophy while attenuating cellular proliferation. We also report an upregulation of MEK and ERK activation suggestive of a proliferative phenotype. Hhowever, the proliferative response appears to be aborogated by enhanced antimitogenic cytokine VEGF, NO secretion and downregulation of Cdk expression. Although exogenous VEGF alone is not sufficient to promote the quiescent VSMC phenotype, we provide evidence suggesting that strain is a necessary component to induce VSMC response to the antimitogenic effects of VEGF. Taken together these data indicate that VEGF plays a critical role in mechanical strain-induced VSMC proliferation and vessel wall remodeling. Whether VEGF and/or NO inhibit signaling distal to Erk 1/2 is currently under investigation.
    • Cycloartane- And Lanostane-Type Triterpenoids from the Resin of Parthenium argentatum AZ-2, a Byproduct of Guayule Rubber Production

      Xu, Y.-M.; Madasu, C.; Liu, M.X.; Wijeratne, E.M.K.; Dierig, D.; White, B.; Molnár, I.; Gunatilaka, A.A.L.; Southwest Center for Natural Products Research, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona (American Chemical Society, 2021)
      A total of 12 new cycloartane- and lanostane-type triterpenoids including 16-deoxyargentatin A (1), 16-deoxyisoargentatin A (2), 7-oxoisoargentatin A (3), 24-epi-argentatin H (4), 24-O-p-anisoylargentatin C (5), 24-O-trans-cinnamoylargentatin C (6), 16-dehydroargentatin C (7), 16,17(20)-didehydroargentatin C (8), isoargentatin C (9), isoargentatin H (10), 3-epi-quisquagenin (11), and isoquisquagenin (12) together with 10 known triterpenoids (13-22) were isolated from the resin of Parthenium argentatum AZ-2 obtained as a byproduct of Bridgestone guayule rubber production. The structures of new triterpenoids 1-12 and argentatin H (13), which has previously been characterized as its diacetate (23), were elucidated by extensive analysis of their spectroscopic data and chemical conversions, and the known compounds 14-22 were identified by comparison of their spectroscopic data with those reported. Of these, 13, 14, and 18 exhibited weak cytotoxic activity for several cancer cell lines. © 2021 American Chemical Society. All rights reserved.
    • Cystic Fibrosis Transmembrane Conductance Regulator Genotype, Not Circulating Catecholamines, Influences Cardiovascular Function in Patients with Cystic Fibrosis

      Bisch, Alexander L; Wheatley, Courtney M; Baker, Sarah E; Peitzman, Elizabeth R; Van Iterson, Erik H; Laguna, Theresa A; Morgan, Wayne J; Snyder, Eric M; Univ Arizona, Arizona Resp Ctr (SAGE PUBLICATIONS LTD, 2019-03-29)
      BACKGROUND: Cystic fibrosis (CF) is a genetic disease affecting multiple organ systems of the body and is characterized by mutation in the gEne coding for the cystic fibrosis transmembrane conductance regulator (CFTR). Previous work has shown that a single dose of a beta-agonist increases cardiac output (Q) and stroke volume (SV) and decreases systemic vascular resistance (SVR) in healthy subjects. This effect is attenuated in patients with CF; however, the mechanism is unknown. Potential explanations for this decreased cardiovascular response to a beta-agonist in CF include inherent cardiovascular deficits secondary to the CFTR mutation, receptor desensitization from prolonged beta-agonist use as part of clinical care, or inhibited drug delivery to the bloodstream due to mucus buildup in the lungs. This study sought to determine the effects of endogenous epinephrine (EPI) and norepinephrine (NE) on cardiovascular function in CF and to evaluate the relationship between cardiovascular function and CFTR F508del mutation. METHODS: A total of 19 patients with CF and 31 healthy control subjects completed an assessment of Q (C2H2 rebreathing), SV (calculated from Q and heart rate [HR]), Q and SV indexed to body surface area (BSA. Ql. and SVI. respectively). SVR (through assessment of Q and mean arterial blood pressure [MAP]). and HR (from 12-lead electrocardiogram [ECG]) at rest along with plasma measures of EPI and NE. We compared subjects by variables of cardiovascular function relative to EPI and NE, and also based on genetic variants of the F508del mutation (homozygous deletion for F508del. heterozygous deletion for F508del, or no deletion of F508del). RESULTS: Cystic fibrosis patients demonstrated significantly lower BSA (CF = 1.71 +/- 0.05 m(2) vs healthy = 1.84 +/- 0.04 m(2), P = .03) and SVI (CF = 30.6 +/- 2.5 mL/beat/m(2) vs healthy = 39.9 +/- 2.5 mL/beat/m(2) , P = .02) when compared with healthy subjects. Cystic fibrosis patients also demonstrated lower Q (CF = 4.58 +/- 0.36 L/min vs healthy = 5.71 +/- 0.32 L/min, P = .03) and SV (CF = 54 +/- 5.5 mL/beat vs healthy = 73.3 +/- 4.5 mL/beat. P = .01), and a higher HR (CF = 93.2 +/- 3.9 bpm vs healthy = 80.5 +/- 2.7 bpm, P < .01) and SVR (CF = 2082 +/- 156 dynes(*)s/cm(-5) vs healthy = 1616 +/- 74 dynes*s/cm(-5), P= .01) compared with healthy subjects. Furthermore. CF patients demonstrated a lower SV (P < .01) corrected for NE when compared with healthy subjects. No significant differences were seen in HR or Q relative to NE. or SVR relative to EPI. Differences were seen in SV(F-(2,F-14) = 7.982, P < .01) and SV index (F-(2(,14)) = 2.913, P = .08) when patients with CF were stratified according to F508del mutation (number of deletions). CONCLUSIONS: Individuals with CF have lower cardiac and peripheral hemodynamic function parameters at rest. Furthermore, these results suggest that impairment in cardiovascular function is likely the result of F508del CFTR genotype, rather than receptor desensitization or inhibited drug delivery.
    • Cytochrome P450 metabolism of the post-lanosterol intermediates explains enigmas of cholesterol synthesis.

      Ačimovič, Jure; Goyal, Sandeep; Košir, Rok; Goličnik, Marko; Perše, Martina; Belič, Ales; Urlep, Žiga; Guengerich, F Peter; Rozman, Damjana; Univ Arizona, Dept Chem & Biochem (NATURE PUBLISHING GROUP, 2016)
      Cholesterol synthesis is among the oldest metabolic pathways, consisting of the Bloch and Kandutch-Russell branches. Following lanosterol, sterols of both branches are proposed to be dedicated to cholesterol. We challenge this dogma by mathematical modeling and with experimental evidence. It was not possible to explain the sterol profile of testis in cAMP responsive element modulator tau (Crem τ) knockout mice with mathematical models based on textbook pathways of cholesterol synthesis. Our model differs in the inclusion of virtual sterol metabolizing enzymes branching from the pathway. We tested the hypothesis that enzymes from the cytochrome P450 (CYP) superfamily can participate in the catalysis of non-classical reactions. We show that CYP enzymes can metabolize multiple sterols in vitro, establishing novel branching points of cholesterol synthesis. In conclusion, sterols of cholesterol synthesis can be oxidized further to metabolites not dedicated to production of cholesterol. Additionally, CYP7A1, CYP11A1, CYP27A1, and CYP46A1 are parts of a broader cholesterol synthesis network.
    • Cytokine Release, Determined by a Multiplex Cytokine Assay, in Response to Coccidioidal Antigen Stimulation of Whole Blood among Subjects with Recently Diagnosed Primary Pulmonary Coccidioidomycosis

      Ampel, Neil M.; Robey, Ian; Nguyen, Chinh T.; Roller, Brentin; August, Jessica; Knox, Kenneth S.; Pappagianis, Demosthenes; Univ Arizona, Coll Med, Div Infect Dis; Univ Arizona, Coll Med, Div Pulm Med (AMER SOC MICROBIOLOGY, 2018)
      The elements of the cellular immune response in human coccidioidomycosis remain undefined. We examined the ex vivo release of an array of inflammatory proteins in response to incubation with a coccidioidal antigen preparation to ascertain which of these might be associated with diagnosis and outcome. Patients with a recent diagnosis of primary pulmonary coccidioidomycosis and a control group of healthy subjects were studied. Blood samples were incubated for 18 h with T27K, a soluble coccidioidal preparation containing multiple glycosylated antigens, and the supernatant was assayed for inflammatory proteins using the multiplex Luminex system. The presentation and course of illness were compared to the levels of the inflammatory proteins. Among the 31 subjects studied, the median time from diagnosis to assay was 15 days. Of the 30 inflammatory proteins measured, the levels of only 7 proteins, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 receptor alpha (IL-1RA), interleukin-1 beta (IL-1 beta), interferon gamma (IFN-gamma), IL-2, IL-13, and tumor necrosis factor alpha (TNF-alpha), were more than 10-fold above the levels seen without antigen stimulation. The levels of IFN-gamma and IL-2 were significantly elevated in those subjects not receiving triazole antifungal therapy compared to those who were receiving triazole antifungal therapy. While the levels of IL-1RA were nonspecifically elevated, elevated levels of IL-13 were seen only in those with active pulmonary coccidioidomycosis. Only six cytokines were specifically increased in subjects with recently diagnosed primary pulmonary coccidioidomycosis. While IFN-gamma, IL-2, and TNF-alpha have been previously noted, the finding of elevated levels of the innate cytokines GM-CSF and IL-1 beta could suggest that these, as well as IL-13, are early and specific markers for pulmonary coccidioidomycosis. IMPORTANCE Coccidioidomycosis, commonly known as Valley fever, is a common pneumonia in the southwestern United States. In this paper, we examined the release of 30 inflammatory proteins in whole-blood samples obtained from persons with coccidioidal pneumonia after the blood samples were incubated with a preparation made from the causative fungus, Coccidioides. We found that six of these proteins, all cytokines, were specifically released in high concentrations in these patients. Three of the cytokines were seen very early in disease, and an assay for all six might serve as a marker for the early diagnosis of Valley fever.