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Staley, B K, Irvine KD.  2010.  Warts and yorkie mediate intestinal regeneration by influencing stem cell proliferation. Current biology : CB. 20:1580-7. AbstractWebsite
Homeostasis in the Drosophila midgut is maintained by stem cells [1, 2]. The intestinal epithelium contains two types of differentiated cells that are lost and replenished: enteroendocrine (EE) cells and enterocytes (ECs). Intestinal stem cells (ISCs) are the only cells in the adult midgut that proliferate [3, 4], and ISC divisions give rise to an ISC and an enteroblast (EB), which differentiates into an EC or an EE cell [3-5]. If the midgut epithelium is damaged, then ISC proliferation increases [6-12]. Damaged ECs express secreted ligands (Unpaired proteins) that activate Jak-Stat signaling in ISCs and EBs to promote their proliferation and differentiation [7, 9, 13, 14]. We show that the Hippo pathway components Warts and Yorkie mediate a transition from low- to high-level ISC proliferation to facilitate regeneration. The Hippo pathway regulates growth in diverse organisms and has been linked to cancer [15, 16]. Yorkie is activated in ECs in response to tissue damage or activation of the damage-sensing Jnk pathway. Activation of Yorkie promotes expression of unpaired genes and triggers a nonautonomous increase in ISC proliferation. Our observations uncover a role for Hippo pathway components in regulating stem cell proliferation and intestinal regeneration.
Smith, PF, Hunt L, Laursen AB, Sagar V, Kaushik S, Calvinho KU, Marotta G, Mosconi E, De Angelis F, Dismukes GC.  2015.  Water Oxidation by the [Co4O4(OAc)4(py)4](+) Cubium is Initiated by OH(-) Addition.. J Am Chem Soc. 137(49):15460-15468. Abstract
The cobalt cubium Co4O4(OAc)4(py)4(ClO4) (1A(+)) containing the mixed valence [Co4O4](5+) core is shown by multiple spectroscopic methods to react with hydroxide (OH(-)) but not with water molecules to produce O2. The yield of reaction products is stoichiometric (>99.5%): 41A(+) + 4OH(-) → O2 + 2H2O + 41A. By contrast, the structurally homologous cubium Co4O4(trans-OAc)2(bpy)4(ClO4)3, 1B(ClO4)3, produces no O2. EPR/NMR spectroscopies show clean conversion to cubane 1A during O2 evolution with no Co(2+) or Co3O4 side products. Mass spectrometry of the reaction between isotopically labeled μ-(16)O(bridging-oxo) 1A(+) and (18)O-bicarbonate/water shows (1) no exchange of (18)O into the bridging oxos of 1A(+), and (2) (36)O2 is the major product, thus requiring two OH(-) in the reactive intermediate. DFT calculations of solvated intermediates suggest that addition of two OH(-) to 1A(+) via OH(-) insertion into Co-OAc bonds is energetically favored, followed by outer-sphere oxidation to intermediate [1A(OH)2](0). The absence of O2 production by cubium 1B(3+) indicates the reactive intermediate derived from 1A(+) requires gem-1,1-dihydoxo stereochemistry to perform O-O bond formation. Outer-sphere oxidation of this intermediate by 2 equiv of 1A(+) accounts for the final stoichiometry. Collectively, these results and recent literature (Faraday Discuss., doi:10.1039/C5FD00076A and J. Am. Chem. Soc. 2015, 137, 12865-12872) validate the [Co4O4](4+/5+) cubane core as an intrinsic catalyst for oxidation of hydroxide by an inner-sphere mechanism.
Robinson, DM, Go Y B, Greenblatt M, Dismukes CG.  2010.  Water Oxidation by λ-MnO2: Catalysis by the Cubical Mn4O4 Subcluster Obtained by Delithiation of Spinel LiMn2O4. Journal of the American Chemical Society. 132:11467-11469. AbstractWebsite
Kolling, DR, Cox N, Ananyev GM, Pace RJ, Dismukes CG.  2012.  What are the oxidation states of manganese required to catalyze photosynthetic water oxidation? Biophysical journal. 103(2):313-22. Abstract
Photosynthetic O(2) production from water is catalyzed by a cluster of four manganese ions and a tyrosine residue that comprise the redox-active components of the water-oxidizing complex (WOC) of photosystem II (PSII) in all known oxygenic phototrophs. Knowledge of the oxidation states is indispensable for understanding the fundamental principles of catalysis by PSII and the catalytic mechanism of the WOC. Previous spectroscopic studies and redox titrations predicted the net oxidation state of the S(0) state to be (Mn(III))(3)Mn(IV). We have refined a previously developed photoassembly procedure that directly determines the number of oxidizing equivalents needed to assemble the Mn(4)Ca core of WOC during photoassembly, starting from free Mn(II) and the Mn-depleted apo-WOC complex. This experiment entails counting the number of light flashes required to produce the first O(2) molecules during photoassembly. Unlike spectroscopic methods, this process does not require reference to synthetic model complexes. We find the number of photoassembly intermediates required to reach the lowest oxidation state of the WOC, S(0), to be three, indicating a net oxidation state three equivalents above four Mn(II), formally (Mn(III))(3)Mn(II), whereas the O(2) releasing state, S(4), corresponds formally to (Mn(IV))(3)Mn(III). The results from this study have major implications for proposed mechanisms of photosynthetic water oxidation.
Smith, PF, Kaplan C, Sheats JE, Robinson DM, McCool NS, Mezle N, Dismukes CG.  2014.  What determines catalyst functionality in molecular water oxidation? Dependence on ligands and metal nuclearity in cobalt clusters. Inorganic chemistry. 53(4):2113-21. Abstract
The metal-oxo M4O4 "cubane" topology is of special significance to the field of water oxidation as it represents the merging of bioinspired structural principles derived from natural photosynthesis with successful artificial catalysts known to date. Herein, we directly compare the rates of water oxidation/O2 evolution catalyzed by six cobalt-oxo clusters including the Co4O4 cubanes, Co4O4(OAc)4(py)4 and [Co4O4(OAc)2(bpy)4](2+), using the common Ru(bpy)3(2+)/S2O8(2-) photo-oxidant assay. At pH 8, the first-order rate constants for these cubanes differ by 2-fold, 0.030 and 0.015 s(-1), respectively, reflecting the number of labile carboxylate sites that allow substrate water binding in a pre-equilibrium step before O2 release. Kinetic results reveal a deprotonation step occurs on this pathway and that two electrons are removed before O2 evolution occurs. The Co4O4 cubane core is shown to be the smallest catalytic unit for the intramolecular water oxidation pathway, as neither "incomplete cubane" trimers [Co3O(OH)3(OAc)2(bpy)3](2+) and [Co3O(OH)2(OAc)3(py)5](2+) nor "half cubane" dimers [Co2(OH)2(OAc)3(bpy)2](+) and [Co2(OH)2(OAc)3(py)4](+) were found capable of evolving O2, despite having the same ligand sets as their cubane counterparts. Electrochemical studies reveal that oxidation of both cubanes to formally Co4(3III,IV) (0.7 V vs Ag/AgCl) occurs readily, while neither dimers nor trimers are oxidized below 1.5 V, pointing to appreciably greater charge delocalization in the [Co4O4](5+) core. The origin of catalytic activity by Co4O4 cubanes illustrates three key features for water oxidation: (1) four one-electron redox metals, (2) efficient charge delocalization of the first oxidation step across the Co4O4 cluster, allowing for stabilization of higher oxidizing equivalents, and (3) terminal coordination site for substrate aquo/oxo formation.
Boucher, HW, Ambrose PG, Chambers HF, Ebright RH, Jezek A, Murray BE, Newland JG, Ostrowsky B, Rex JH.  2017.  White Paper: Developing Antimicrobial Drugs for Resistant Pathogens, Narrow-spectrum Indications, and Unmet Needs.. Journal of Infectious Diseases. 216:226-238. Abstract
Despite progress in antimicrobial drug development, a critical need persists for new, feasible pathways to develop antibacterial agents to treat people infected with drug-resistant bacteria. Infections due to resistant Gram-negative bacilli continue to cause unacceptable morbidity and mortality. Antibacterial agents have been traditionally studied in non-inferiority clinical trials that focus on one site of infection (eg, complicated urinary tract infections, intra-abdominal infections), yet these designs may not be optimal, and often are not feasible, for study of infections caused by drug-resistant bacteria. Over the past several years, multiple stakeholders have worked to develop consensus regarding paths forward with a goal of facilitating timely conduct of antimicrobial development. Here we advocate for a novel and pragmatic approach and, towards this end, present feasible trial designs for antibacterial agents that could enable conduct of narrow-spectrum, organism-specific clinical trials and ultimately approval of critically needed new antibacterial agents.
Liu, Z, Li X, Wang T, Messing J, Xu J-H.  2015.  The Wukong Terminal-Repeat Retrotransposon in Miniature (TRIM) Elements in Diverse Maize Germplasm.. G3 (Bethesda, Md.). 5(8):1585-92. AbstractWebsite
TRIMs (terminal-repeat retrotransposons in miniature), which are characterized by their small size, have been discovered in all investigated vascular plants and even in animals. Here, we identified a highly conservative TRIM family referred to as Wukong elements in the maize genome. The Wukong family shows a distinct pattern of tandem arrangement in the maize genome suggesting a high rate of unequal crossing over. Estimation of insertion times implies a burst of retrotransposition activity of the Wukong family after the allotetraploidization of maize. Using next-generation sequencing data, we detected 87 new Wukong insertions in parents of the maize NAM population relative to the B73 reference genome and found abundant insertion polymorphism of Wukong elements in 75 re-sequenced maize lines, including teosinte, landraces, and improved lines. These results suggest that Wukong elements possessed a persistent retrotransposition activity throughout maize evolution. Moreover, the phylogenetic relationships among 76 maize inbreds and their relatives based on insertion polymorphisms of Wukong elements should provide us with reliable molecular markers for biodiversity and genetics studies.