Single crystals of the m = 8 member of the low-dimensional monophosphate tungsten bronzes (PO2)4(WO3)2m family were grown by chemical vapour transport technique and the high crystalline quality obtained allowed a reinvestigation of the physical and structural properties. Resistivity measurements revealed three anomalies at TC1 = 258 K, TC2 = 245 K and TC3 = 140 K, never observed until now. Parallel X-ray diffraction investigations showed a specific signature associated with three structural transitions, i.e. the appearance of different sets of satellite reflections below TC1, TC2 and TC3. Several harmonics of intense satellite reflections were observed, reflecting the non-sinusoidal nature of the structural modulations and a strong electron–phonon coupling in the material. These transitions could be associated with the formation of three successive unconventional charge density wave states.

Bone crystallite chemistry and structure change during bone maturation. However, these properties of bone can also be affected by limited uptake of the chemical constituents of the mineral by the animal. This makes probing the effect of bone-mineralization-related diseases a complicated task. Here it is shown that the combination of vibrational spectroscopy with two-dimensional X-ray diffraction can provide unparalleled information on the changes in bone chemistry and structure associated with different bone pathologies (phosphate deficiency) and/or health conditions (pregnancy, lactation). Using a synergistic analytical approach, it was possible to trace the effect that changes in the remodelling regime have on the bone mineral chemistry and structure in normal and mineral-deficient (hypophosphatemic) mice. The results indicate that hypophosphatemic mice have increased bone remodelling, increased carbonate content and decreased crystallinity of the bone mineral, as well as increased misalignment of crystallites within the bone tissue. Pregnant and lactating mice that are normal and hypophosphatemic showed changes in the chemistry and misalignment of the apatite crystals that can be related to changes in remodelling rates associated with different calcium demand during pregnancy and lactation.

Mycobacterium tuberculosis produces glycogen (also known as α-glucan) to help evade human immunity. This pathogen uses the GlgE pathway to generate glycogen rather than the more well known glycogen synthase GlgA pathway, which is absent in this bacterium. Thus, the building block for this glucose polymer is α-maltose-1-phosphate rather than an NDP-glucose donor. One of the routes to α-maltose-1-phosphate is now known to involve the GlgA homologue GlgM, which uses ADP-glucose as a donor and α-glucose-1-phosphate as an acceptor. To help compare GlgA (a GT5 family member) with GlgM enzymes (GT4 family members), the X-ray crystal structure of GlgM from Mycobacterium smegmatis was solved to 1.9 Å resolution. While the enzymes shared a GT-B fold and several residues responsible for binding the donor substrate, they differed in some secondary-structural details, particularly in the N-terminal domain, which would be expected to be largely responsible for their different acceptor-substrate specificities.

The cationic cyclo­metallated iridium(III) complex [Ir(C9H7N2)2(C12H8N2)](PF6) has been synthesized and crystallized by the inter-diffusion method. It contains an unknown number of solvent mol­ecules and has a different space-group symmetry (C2/c) structure than its solvatomorph (P21/c).

The cationic complex in the title compound, [Ir(C9H7N2)2(C12H8N2)]PF6, comprises two phenylpyrazole (ppz) cyclometallating ligands and one 1,10-phenanthroline (phen) ancillary ligand. The asymmetric unit consists of one [Ir(ppz)2(phen)]+ cation and one [PF6]− counter-ion. The central IrIII ion is six-coordinated by two N atoms and two C atoms from the two ppz ligands as well as by two N atoms from the phen ligand within a distorted octahedral C2N4 coordination set. In the crystal structure, the [Ir(ppz)2(phen)]+ cations and PF6− counter-ions are connected with each other through weak intermolecular C—H...F hydrogen bonds. Additional C—H...π interactions between the rings of neighbouring cations consolidate the three-dimensional network. Electron density associated with additional disordered solvent molecules inside cavities of the structure was removed with the SQUEEZE procedure in PLATON [Spek (2015). Acta Cryst. C71, 9–18]. The given chemical formula and other crystal data do not take into account the unknown solvent molecule(s). The title compound has a different space-group symmetry (C2/c) from its solvatomorph (P21/c) comprising 1.5CH2Cl2 solvent molecules per ion pair.

The crystal structures of caesium di­hydrogen arsenate(V) bis­[tri­hydrogen arsen­ate(V)], Cs(H2AsO4)(H3AsO4)2, ammonium di­hydrogen arsenate(V) tri­hydrogen arsenate(V), NH4(H2AsO4)(H3AsO4), and dilithium bis­(di­hydrogen phosphate), Li2(H2PO4)2, were solved from single-crystal X-ray diffraction data. NH4(H2AsO4)(H3AsO4), which was hydro­thermally synthesized (T = 493 K), is homeotypic with Rb(H2AsO4)(H3AsO4), while Cs(H2AsO4)(H3AsO4)2 crystallizes in a novel structure type and Li2(H2PO4)2 represents a new polymorph of this composition. The Cs and Li compounds grew at room temperature from highly acidic aqueous solutions. Li2(H2PO4)2 forms a three-dimensional (3D) framework of PO4 tetra­hedra sharing corners with Li2O6 dimers built of edge-sharing LiO4 groups, which is reinforced by hydrogen bonds. The two arsenate compounds are characterized by a 3D network of AsO4 groups that are connected solely via multiple strong hydrogen bonds. A statistical evaluation of the As—O bond lengths in singly, doubly and triply protonated AsO4 groups gave average values of 1.70 (2) Å for 199 As—OH bonds, 1.728 (19) Å for As—OH bonds in HAsO4 groups, 1.714 (12) Å for As—OH bonds in H2AsO4 groups and 1.694 (16) Å for As—OH bonds in H3AsO4 groups, and a grand mean value of 1.667 (18) Å for As—O bonds to nonprotonated O atoms.

Phosphate is added to domestic drinking water to reduce lead levels in the UK, to help meet EU Drinking Water Directive standards. New research has now found that phosphate can also reduce the amount of copper in domestic sewage by more than a third. This method could help Member States meet forthcoming “safe” levels for water discharged to the environment, under forthcoming EU Water Framework Directive (WFD) proposals.

A glycerol derivative which is effective to reduce blood pressure and has the formula: ##STR1## wherein R1 is an alkyl group having 10-22 carbon atoms, R2 is a lower acyl group or benzoyl, each of R3 and R4 independently is hydrogen or a straight or branched chain alkyl group having 1-6 carbon atoms; each of R5, R6 and R7 independently is hydrogen, a straight or branched chain alkyl group having 1-6 carbon atoms, an aryl group or an aralkyl group; and each of m and n independently is 0 or a positive integer under the condition of m+n=2-8.

The present invention relates to novel heterocycle-substituted diphosphonic acids, and the pharmaceutically-acceptable salts and esters thereof, in which the diphosphonate-substituted carbon atom moiety is attached to a carbon atom in a nitrogen-containing six membered ring heterocycle, preferably a piperidine ring. The heterocycle-substituted diphosphonic acid compounds have the general structure: ##STR1## wherein Z is a nitrogen-containing six membered ring heterocycle moiety selected from piperidinyl, diazinyl and triazinyl; m, n and m+n are from 0 to 10; Q is a covalent bond or a moiety selected from oxygen, sulfur or nitrogen; and R1, R2, R3 and R4 are substituent groups.The present invention further relates to pharmaceutical compositions containing these novel compounds. Finally this invention relates to methods for treating or preventing diseases characterized by abnormal calcium and phosphate metabolism by utilizing a compound or pharmaceutical composition of the present invention.

The invention provides an improved process for the synthesis of compounds carrying at least one phosphate group, especially polyalkylene glycol phosphate compounds, said process comprising the steps of: (a) reacting a compound containing at least one primary alcohol moiety with a diaryl- or diaralkyl-halophosphate whereby to form the corresponding diaryl- or diaralkyl-phosphate ester; (b) reductively cleaving the resulting product; and (c) if desired, repeating steps (a) and (b) with the product of step (b) whereby to produce a compound carrying two or more phosphate groups. Advantages of the process in accordance with the invention are that this avoids the production of by-products and results in products which are low in impurities. Also provided are novel diaryl- and diaralkyl-phosphate ester compounds, in particular polyethylene glycol diphenylphosphate ester and derivatives thereof.

The invention relates to a process for preparing triethyl phosphate by reacting phosphorus oxychloride with a greater than stoichiometric quantity of ethanol under reduced pressure at temperatures of from 0 to 50° C. in a reaction vessel, wherein a) the volatile components resulting from the reaction are predominantly condensed by means of a reflux condenser and the remaining volatile components are passed into a scrubber filled with water,b) after the end of the reaction, the reaction mixture is separated distillatively in an outgassing column into a top product and a bottom product which predominantly comprises triethyl phosphate,c) the top product of the outgassing column is combined with the contents of the scrubber andd) the contents of the scrubber are separated distillatively in an azeotropic distillation to obtain water and ethanol as top product and the ethanol, preferably after dewatering, is preferably returned to the reaction.

Degradation of phosphate esters, particularly neurotoxins and pesticides, is performed using high oxidative state molybdenum complexes, more particularly molybdenum(VI) complexes. A molybdenum(VI) complex is dissolved in water and then reacted with a phosphate ester. The phosphate esters can include, but are not limited to, VX, VE, VG, VM, GB, GD, GA, GF, parathion, paraoxon, triazophos, oxydemeton-methyl, chlorpyrifos, fenitrothion and pirimiphos-methyl, representing both chemical warfare agents as well as pesticides and insecticides.

This invention relates to a process for preparing an oligonucleotide 5'-triphosphate. The process comprises the steps of: (a) synthesizing an oligonucleotide having a 5' hydroxyl moiety; (b) reacting the 5' hydroxyl moiety with a reagent of formula I: to convert the 5' hydroxyl moiety to a 5'-H-phosphonate, wherein R1 and R2 are each independently selected from the group consisting of haloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycle, and substituted heterocycle, acyl, phosphoryl, substituted alkyl acyl, substituted heteroalkyl acyl, substituted aryl acyl or substituted heteroaryl acyl, substituted alkyl phosphoryl, substituted heteroalkyl acyl, substituted aryl phosphoryl, and substituted heteroaryl phosphoryl; (c) activating the H-phosphonate of step (b) by reacting the H-phosphonate with a silylating agent, a halogenated oxidizing agent, a nitrogen-containing heteroaryl, or a combination thereof, to form an activated H-phosphonate; and (d) treating the oligonucleotide having an activated H-phosphonate from step (c) with a poly(alkylammonium)pyrophosphate.

Compounds which are trehalose-6-phosphate or trehalose-6-phosphonate precursors of formula (I) or agriculturally acceptable salts thereof are provided: (I) The compounds are useful in increasing starch production in plants.

A method of treating cancer through use of guanosine 3',5'-cyclic monophosphate (cyclic GMP). Cyclic GMP decreases the number of human breast cancer and prostate adenocarcinoma as well as small-cell and squamous lung cells in culture by 30% (1 μM), 84% (1 mM), 31% (1 μM), and 30% (1 μM), respectively. Cyclic GMP decreases DNA synthesis in human pancreatic, breast, and prostate adenocarcinomas as well as small-cell and squamous cell carcinomas of the lung at its 1 μM concentration by 51%, 54%, 56%, 50% and 52%, respectively. Cyclic GMP when infused for one week decreases the tumor volume of human pancreatic adenocarcinomas in athymic mice 95% compared to untreated animals with human pancreatic adenocarcinomas.

The present invention provides a phosphate group-containing resin comprising, as polymerized units, a polymerizable unsaturated polyester having at least one phosphate group and/or having at least one phosphoric acid group, a (meth)acrylate based polymerizable monomer, and an alkoxylated (meth)acrylic acid polymerizable monomer; and a use of the phosphate-group containing resin as a treating agent of a metallic pigment or an inorganic pigment, especially used in a water-based coating composition.

Disclosed are new members of a class of non-lipid small molecule inhibitors which interfere with the interaction between phosphoinositol-3,4,5-triphosphate (PIP3) and pleckstrin homology (PH) domains. These molecules target a broad range of PIP3-dependent signaling events in vitro and exert significant anti-tumor activity in vivo, with improved activity and selectivity toward particular PH domains. The small molecule inhibitors of the invention can be used alone or together with tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) or other cancer medicament to treat cancer. Small molecule inhibitors of the invention act synergistically in combination with TRAIL and with other Akt inhibitors in treating cancer. Pharmaceutical compositions and methods for treating cancer are provided.

An object the invention is to provide a phosphorus pentafluoride producing process wherein phosphorus pentafluoride is separated/extracted from a pentavalent phosphorus compound or a solution thereof, or a composition obtained by allowing the pentavalent phosphorus compound or the solution thereof to react with hydrogen fluoride, thereby producing phosphorus pentafluoride; and a phosphate hexafluoride producing process wherein the resultant phosphorus pentafluoride is used as raw material to produce a phosphate hexafluoride high in purity. The present invention relates to a process for producing phosphorus pentafluoride, wherein a carrier gas is brought into contact with either of the following one: a pentavalent phosphorus compound, a solution thereof, or a solution in which a composition obtained by allowing the pentavalent phosphorus compound or the solution thereof to react with hydrogen fluoride is dissolved, thereby a phosphorus pentafluoride is extracted into the career gas.

In an embodiment, the cement compositions comprise: (i) hydraulic cement, wherein the hydraulic cement has a ratio of CaO to SiO2 in the range of 2.0 to 4.0; and (ii) a water-soluble metaphosphate in a concentration of at least 2.5% bwoc. In another embodiment, the cement compositions comprise: (i) hydraulic cement, wherein the hydraulic cement has a ratio of CaO to SiO2 of less than 2.0; and (ii) a water-soluble metaphosphate; wherein any alkali nitrate is in a concentration of less than 2% bwoc; and wherein any alkali hydroxide, alkali carbonate, or alkali citrate is in a concentration of less than 0.2% bwoc. Methods of cementing in a well comprising forming either of such cement compositions and introducing it into the well are provided.

A method for slicing a workpiece into wafers in which a polyphosphate solution is applied to the workpiece during the slicing process. The method comprises the steps of positioning the workpiece, such as a silicon ingot, in the vicinity of a wire saw that can cut through the workpiece without the use of an abrasive slurry; causing an aqueous polyphosphate solution to contact the workpiece; and causing the wire saw to cut into the workpiece while the polyphosphate solution is in contact with the workpiece. After the workpiece has been cut into wafers, the polyphosphate solution is rinsed off of the wafers. Preferably, the wire saw used in this method is a diamond wire saw.

A method and processes to solubilize and transform phosphorus contents of rock phosphate (RP) into bio-organo-phosphate (BOP) fertilizer have been developed and integrated. The methods include collecting and sorting of organic wastes; blending with RP; subjecting the blend to biocomposting; collection, isolation, selection and growth optimization of consortia of efficient phosphorus solubilizing microorganisms (PSM) and novel plant growth regulating microorganisms (PGRM); where in PSM produce organic acids and other organic compounds using compost substrate at mesophillic stage, whereas the organic acids released during composting also act in synergism of PSM, thus forming a carbon rich acidic culture resulting in the solubilization of rock phosphate.

The invention employs composites of zeolite and ferric oxide hydroxide for removal of inorganic nitrogen and phosphorus wastes from animal environments.

A water-insoluble phosphate fertilizer, methods of producing, and methods of using the same are provided. The fertilizer may comprise at least one alkaline earth metal selected from calcium and magnesium and optionally at least one nutrient ion selected from the group consisting of potassium, ammonium, zinc, iron, manganese, copper, boron, chlorine, iodine, molybdenum or selenium. The fertilizer compounds are preferably water-insoluble, dilute acid-soluble, and free-flowing powders.

The present invention relates to oral and dental care and cleaning agents comprising an aqueous dispersion of a phosphate-containing and/or phosphonate-containing polyurethane polymer and anionic surfactant(s), to tooth cleaning methods using these agents, and to the use of oral and dental care and cleaning agents comprising an aqueous dispersion of a phosphate-containing and/or phosphonate-containing polyurethane polymer and anionic surfactant(s) to reduce the restaining of teeth and/or to reduce biofilm development on dental surfaces and/or to reduce the adhesion of bacteria to dental surfaces and/or to extend the antibacterial action of antibacterial substances.

A composite particle and a population of particles comprising a water-insoluble polyphosphate composition, methods of producing, and methods of using the same are provided. The polyphosphate composition may comprise at least one alkaline earth metal selected from calcium and magnesium and optionally at least one nutrient ion selected from the group consisting of potassium, ammonium, zinc, iron, manganese, copper, boron, chlorine, iodine, molybdenum, selenium or sulfur.

The present disclosure provides robust, high-throughput, and clinically applicable methods for simultaneously separating and quantifying the biologically active forms of Vitamin B1 (TPP) and Vitamin B6 (PLP) from human whole blood.

BACKGROUND Glucose-6-phosphate dehydrogenase (G6PD) deficiency decreases the ability of red blood cells (RBCs) to withstand oxidative stress. Refrigerated storage of RBCs induces oxidative stress. We hypothesized that G6PD-deficient donor RBCs would have inferior storage quality for transfusion as compared with G6PD-normal RBCs.METHODS Male volunteers were screened for G6PD deficiency; 27 control and 10 G6PD-deficient volunteers each donated 1 RBC unit. After 42 days of refrigerated storage, autologous 51-chromium 24-hour posttransfusion RBC recovery (PTR) studies were performed. Metabolomics analyses of these RBC units were also performed.RESULTS The mean 24-hour PTR for G6PD-deficient subjects was 78.5% ± 8.4% (mean ± SD), which was significantly lower than that for G6PD-normal RBCs (85.3% ± 3.2%; P = 0.0009). None of the G6PD-normal volunteers (0/27) and 3 G6PD-deficient volunteers (3/10) had PTR results below 75%, a key FDA acceptability criterion for stored donor RBCs. As expected, fresh G6PD-deficient RBCs demonstrated defects in the oxidative phase of the pentose phosphate pathway. During refrigerated storage, G6PD-deficient RBCs demonstrated increased glycolysis, impaired glutathione homeostasis, and increased purine oxidation, as compared with G6PD-normal RBCs. In addition, there were significant correlations between PTR and specific metabolites in these pathways.CONCLUSION Based on current FDA criteria, RBCs from G6PD-deficient donors would not meet the requirements for storage quality. Metabolomics assessment identified markers of PTR and G6PD deficiency (e.g., pyruvate/lactate ratios), along with potential compensatory pathways that could be leveraged to ameliorate the metabolic needs of G6PD-deficient RBCs.TRIAL REGISTRATION ClinicalTrials.gov NCT04081272.FUNDING The Harold Amos Medical Faculty Development Program, Robert Wood Johnson Foundation grant 71590, the National Blood Foundation, NIH grant UL1 TR000040, the Webb-Waring Early Career Award 2017 by the Boettcher Foundation, and National Heart, Lung, and Blood Institute grants R01HL14644 and R01HL148151.

Eiji Kinoshita
Apr 1, 2006; 5:749-757
Technology

The transfer of a phosphate from ATP to a protein substrate, a modification known as protein phosphorylation, is catalyzed by protein kinases. Protein kinases play a crucial role in virtually every cellular activity. Recent studies of atypical protein kinases have highlighted the structural similarity of the kinase superfamily despite notable differences in primary amino acid sequence. Here, using a bioinformatics screen, we searched for putative protein kinases in the intracellular bacterial pathogen Legionella pneumophila and identified the type 4 secretion system effector Lpg2603 as a remote member of the protein kinase superfamily. Employing an array of biochemical and structural biology approaches, including in vitro kinase assays and isothermal titration calorimetry, we show that Lpg2603 is an active protein kinase with several atypical structural features. Importantly, we found that the eukaryote-specific host signaling molecule inositol hexakisphosphate (IP6) is required for Lpg2603 kinase activity. Crystal structures of Lpg2603 in the apo-form and when bound to IP6 revealed an active-site rearrangement that allows for ATP binding and catalysis. Our results on the structure and activity of Lpg2603 reveal a unique mode of regulation of a protein kinase, provide the first example of a bacterial kinase that requires IP6 for its activation, and may aid future work on the function of this effector during Legionella pathogenesis.

The transfer of a phosphate from ATP to a protein substrate, a modification known as protein phosphorylation, is catalyzed by protein kinases. Protein kinases play a crucial role in virtually every cellular activity. Recent studies of atypical protein kinases have highlighted the structural similarity of the kinase superfamily despite notable differences in primary amino acid sequence. Here, using a bioinformatics screen, we searched for putative protein kinases in the intracellular bacterial pathogen Legionella pneumophila and identified the type 4 secretion system effector Lpg2603 as a remote member of the protein kinase superfamily. Employing an array of biochemical and structural biology approaches, including in vitro kinase assays and isothermal titration calorimetry, we show that Lpg2603 is an active protein kinase with several atypical structural features. Importantly, we found that the eukaryote-specific host signaling molecule inositol hexakisphosphate (IP6) is required for Lpg2603 kinase activity. Crystal structures of Lpg2603 in the apo-form and when bound to IP6 revealed an active-site rearrangement that allows for ATP binding and catalysis. Our results on the structure and activity of Lpg2603 reveal a unique mode of regulation of a protein kinase, provide the first example of a bacterial kinase that requires IP6 for its activation, and may aid future work on the function of this effector during Legionella pathogenesis.

Gernot F. Grabner
Apr 29, 2020; 0:jlr.RA119000516v1-jlr.RA119000516
Research Articles

Bis(monoacylglycero)phosphate (BMP), also known as lysobisphosphatidic acid (LBPA), is a phospholipid that promotes lipid sorting in late endosomes/lysosomes by activating lipid hydrolases and lipid transfer proteins. Changes in the cellular BMP content therefore reflect an altered metabolic activity of the endo-lysosomal system. Surprisingly, little is known about the physiological regulation of BMP. In this study, we investigated the effects of nutritional and metabolic factors on BMP profiles of whole tissues and  parenchymal and non-parenchymal cells. Tissue samples were obtained from fed, fasted, two-hours refed, and insulin-treated mice, as well as from mice housed at  5°C, 22°C, or 30°C. These tissues exhibited distinct BMP profiles, which were regulated by the nutritional state in a tissue-specific manner. Insulin treatment was not sufficient to mimic refeeding-induced changes in tissue BMP levels indicating that BMP metabolism is regulated by other hormonal or nutritional factors. Tissue fractionation experiments revealed that fasting drastically elevates BMP levels in hepatocytes and pancreatic cells. Furthermore, we observed that the BMP content in brown adipose tissue strongly depends on housing temperatures. In conclusion, our observations suggest that BMP concentrations adapt to the metabolic state in a tissue-and cell type-specific manner in mice. Drastic changes observed in hepatocytes, pancreatic cells, and brown adipocytes suggest that BMP possesses a role in the functional adaption to nutrient starvation and ambient temperature.

The transfer of a phosphate from ATP to a protein substrate, a modification known as protein phosphorylation, is catalyzed by protein kinases. Protein kinases play a crucial role in virtually every cellular activity. Recent studies of atypical protein kinases have highlighted the structural similarity of the kinase superfamily despite notable differences in primary amino acid sequence. Here, using a bioinformatics screen, we searched for putative protein kinases in the intracellular bacterial pathogen Legionella pneumophila and identified the type 4 secretion system effector Lpg2603 as a remote member of the protein kinase superfamily. Employing an array of biochemical and structural biology approaches, including in vitro kinase assays and isothermal titration calorimetry, we show that Lpg2603 is an active protein kinase with several atypical structural features. Importantly, we found that the eukaryote-specific host signaling molecule inositol hexakisphosphate (IP6) is required for Lpg2603 kinase activity. Crystal structures of Lpg2603 in the apo-form and when bound to IP6 revealed an active-site rearrangement that allows for ATP binding and catalysis. Our results on the structure and activity of Lpg2603 reveal a unique mode of regulation of a protein kinase, provide the first example of a bacterial kinase that requires IP6 for its activation, and may aid future work on the function of this effector during Legionella pathogenesis.

VOLUME 295 (2020) PAGES 4079–4092There was an error in the abstract. “The pyridinium cation hampers uptake of OPs into the central nervous system (CNS)” should read as “The pyridinium cation hampers uptake into the central nervous system (CNS).”

Paris : J.-B. Baillière, 1877.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an important risk factor for neonatal jaundice in Nigeria. It is associated with severe hyperbilirubinemia among infants exposed to icterogenic agents. Elevated bilirubin levels have occasionally been demonstrated in G6PD-deficient infants without exposure to icterogenic agents.

Even without exposure to known icterogens, G6PD-deficient infants have a more rapid hematocrit decline and higher bilirubin levels than their G6PD-intermediate and G6PD-normal counterparts throughout the first week of life. (Read the full article)

Glucose-6-phosphate dehydrogenase deficiency remains a global as well as a North American burden for extreme hyperbilirubinemia and kernicterus and is often unpredictable during the first few days after birth. Newborn screening for this enzyme deficiency is not universally available but debated.

Point-of-care screening, using digital microfluidics, provides accurate, low blood volume, and affordable technology for rapid newborn glucose-6-phosphate dehydrogenase enzyme screening that could guide clinicians before infants’ discharge from well-child nurseries and meet existing American Academy of Pediatrics’ recommendations. (Read the full article)

ABSTRACT

The Candida albicans high-affinity phosphate transporter Pho84 is required for normal Target of Rapamycin (TOR) signaling, oxidative stress resistance, and virulence of this fungal pathogen. It also contributes to C. albicans’ tolerance of two antifungal drug classes, polyenes and echinocandins. Echinocandins inhibit biosynthesis of a major cell wall component, beta-1,3-glucan. Cells lacking Pho84 were hypersensitive to other forms of cell wall stress beyond echinocandin exposure, while their cell wall integrity signaling response was weak. Metabolomics experiments showed that levels of phosphoric intermediates, including nucleotides like ATP and nucleotide sugars, were low in pho84 mutant compared to wild-type cells recovering from phosphate starvation. Nonphosphoric precursors like nucleobases and nucleosides were elevated. Outer cell wall phosphomannan biosynthesis requires a nucleotide sugar, GDP-mannose. The nucleotide sugar UDP-glucose is the substrate of enzymes that synthesize two major structural cell wall polysaccharides, beta-1,3- and beta-1,6-glucan. Another nucleotide sugar, UDP-N-acetylglucosamine, is the substrate of chitin synthases which produce a stabilizing component of the intercellular septum and of lateral cell walls. Lack of Pho84 activity, and phosphate starvation, potentiated pharmacological or genetic perturbation of these enzymes. We posit that low substrate concentrations of beta-d-glucan- and chitin synthases, together with pharmacologic inhibition of their activity, diminish enzymatic reaction rates as well as the yield of their cell wall-stabilizing products. Phosphate import is not conserved between fungal and human cells, and humans do not synthesize beta-d-glucans or chitin. Hence, inhibiting these processes simultaneously could yield potent antifungal effects with low toxicity to humans.

IMPORTANCE Candida species cause hundreds of thousands of invasive infections with high mortality each year. Developing novel antifungal agents is challenging due to the many similarities between fungal and human cells. Maintaining phosphate balance is essential for all organisms but is achieved completely differently by fungi and humans. A protein that imports phosphate into fungal cells, Pho84, is not present in humans and is required for normal cell wall stress resistance and cell wall integrity signaling in C. albicans. Nucleotide sugars, which are phosphate-containing building block molecules for construction of the cell wall, are diminished in cells lacking Pho84. Cell wall-constructing enzymes may be slowed by lack of these building blocks, in addition to being inhibited by drugs. Combined targeting of Pho84 and cell wall-constructing enzymes may provide a strategy for antifungal therapy by which two sequential steps of cell wall maintenance are blocked for greater potency.

Plants have evolved complex physiological and biochemical mechanisms to adapt to a heterogeneous soil phosphorus environment. PHOSPHATE2 (PHO2) is a phosphate (Pi) starvation-signaling regulator involved in maintaining Pi homeostasis in plants. Arabidopsis (Arabidopsis thaliana) PHO2 targets PHOSPHATE TRANSPORTER1 (PHT1) and PHO1 for degradation, whereas rice (Oryza sativa) PHO2 is thought to mediate PHOSPHATE TRANSPORTER TRAFFIC FACILITATOR1 degradation. However, it is unclear whether and how PHO2 is post-translationally regulated. Here, we show that in rice, the CASEIN KINASE2 (OsCK2) catalytic subunit OsCK2α3 interacts with OsPHO2 in vitro and in vivo in vascular tissues cells, and phosphorylates OsPHO2 at Ser-841. Phosphorylated OsPHO2 is degraded more rapidly than native OsPHO2 in cell-free degradation assays. OsPHO2 interacts with OsPHO1 and targets it for degradation through a multivesicular body-mediated pathway. PHO1 mutation partially rescued the pho2 mutant phenotype. Further genetic analysis showed that a nonphosphorylatable version of OsPHO2 rescued the Ospho2 phenotype of high Pi accumulation in leaves better than native OsPHO2. In addition to the previously established role of OsCK2 in negatively regulating endoplasmic reticulum exit of PHT1 phosphate transporters, this work uncovers a role for OsCK2α3 in modulating Pi homeostasis through regulating the phosphorylation status and abundance of OsPHO2 in rice.

Functions of eukaryotic mRNAs are characterized by intramolecular interactions between their ends. We have addressed the question whether 5' and 3' ends meet by diffusion-controlled encounter "through solution" or by a mechanism involving the RNA backbone. For this purpose, we used a translation system derived from Drosophila embryos that displays two types of 5'–3' interactions: Cap-dependent translation initiation is stimulated by the poly(A) tail and inhibited by Smaug recognition elements (SREs) in the 3' UTR. Chimeric RNAs were made consisting of one RNA molecule carrying a luciferase coding sequence and a second molecule containing SREs and a poly(A) tail; the two were connected via a protein linker. The poly(A) tail stimulated translation of such chimeras even when disruption of the RNA backbone was combined with an inversion of the 5'–3' polarity between the open reading frame and poly(A) segment. Stimulation by the poly(A) tail also decreased with increasing RNA length. Both observations suggest that contacts between the poly(A) tail and the 5' end are established through solution, independently of the RNA backbone. In the same chimeric constructs, SRE-dependent inhibition of translation was also insensitive to disruption of the RNA backbone. Thus, tracking of the backbone is not involved in the repression of cap-dependent initiation. However, SRE-dependent repression was insensitive to mRNA length, suggesting that the contact between the SREs in the 3' UTR and the 5' end of the RNA might be established in a manner that differs from the contact between the poly(A) tail and the cap.

VOLUME 295 (2020) PAGES 4079–4092There was an error in the abstract. “The pyridinium cation hampers uptake of OPs into the central nervous system (CNS)” should read as “The pyridinium cation hampers uptake into the central nervous system (CNS).”

Diadenosine tetraphosphate (Ap₄A) is a dinucleotide found in both prokaryotes and eukaryotes. In bacteria, its cellular levels increase following exposure to various stress signals and stimuli, and its accumulation is generally correlated with increased sensitivity to a stressor(s), decreased pathogenicity, and enhanced antibiotic susceptibility. Ap₄A is produced as a by-product of tRNA aminoacylation, and is cleaved to ADP molecules by hydrolases of the ApaH and Nudix families and/or by specific phosphorylases. Here, considering evidence that the recombinant protein YqeK from Staphylococcus aureus copurified with ADP, and aided by thermal shift and kinetic analyses, we identified the YqeK family of proteins (COG1713) as an unprecedented class of symmetrically cleaving Ap₄A hydrolases. We validated the functional assignment by confirming the ability of YqeK to affect in vivo levels of Ap₄A in B. subtilis. YqeK shows a catalytic efficiency toward Ap₄A similar to that of the symmetrically cleaving Ap₄A hydrolases of the known ApaH family, although it displays a distinct fold that is typical of proteins of the HD domain superfamily harboring a diiron cluster. Analysis of the available 3D structures of three members of the YqeK family provided hints to the mode of substrate binding. Phylogenetic analysis revealed the occurrence of YqeK proteins in a consistent group of Gram-positive bacteria that lack ApaH enzymes. Comparative genomics highlighted that yqeK and apaH genes share a similar genomic context, where they are frequently found in operons involved in integrated responses to stress signals.

IMPORTANCE Elevation of Ap₄A level in bacteria is associated with increased sensitivity to heat and oxidative stress, reduced antibiotic tolerance, and decreased pathogenicity. ApaH is the major Ap₄A hydrolase in gamma- and betaproteobacteria and has been recently proposed as a novel target to weaken the bacterial resistance to antibiotics. Here, we identified the orphan YqeK protein family (COG1713) as a highly efficient Ap₄A hydrolase family, with members distributed in a consistent group of bacterial species that lack the ApaH enzyme. Among them are the pathogens Staphylococcus aureus, Streptococcus pneumoniae, and Mycoplasma pneumoniae. By identifying the player contributing to Ap₄A homeostasis in these bacteria, we disclose a novel target to develop innovative antibacterial strategies.

Subjects with low serum HDL cholesterol levels are reported to be susceptible to diabetes, with insulin resistance believed to be the underlying pathological mechanism. Apolipoprotein M (apoM) is a carrier of sphingosine-1-phosphate (S1P), a multifunctional lipid mediator, on HDL, and the pleiotropic effects of HDL are believed to be mediated by S1P. In the current study, we attempted to investigate the potential association between apoM/S1P and insulin resistance. We observed that the serum levels of apoM were lower in patients with type 2 diabetes and that they were negatively correlated with BMI and the insulin resistance index. While deletion of apoM in mice was associated with worsening of insulin resistance, overexpression of apoM was associated with improvement of insulin resistance. Presumably, apoM/S1P exerts its protective effect against insulin resistance by activating insulin signaling pathways, such as the AKT and AMPK pathways, and also by improving the mitochondrial functions through upregulation of SIRT1 protein levels. These actions of apoM/S1P appear to be mediated via activation of S1P1 and/or S1P3. These results suggest that apoM/S1P exerts protective roles against the development of insulin resistance.

A government report has found that selenium contamination is connected to fish deformities, including two-headed trout.

Exports of Calcium Phosphate CMLV in Russia increased to 42.90 USD Million in February from 25.90 USD Million in January of 2020. Exports of Calcium Phosphate CMLV in Russia averaged 139.84 USD Million from 1994 until 2020, reaching an all time high of 622.70 USD Million in December of 2008 and a record low of 5.90 USD Million in January of 1994. Russia accounts for Exports of Calcium Phosphate using cumulative values for each year (CMLV). This page includes a chart with historical data for Russia Exports of Calcium Phosphate CMLV.