Structural chemistry of sulfonated fluorobenzylphosphonate salts. I

A study of the salts of 4-fluoro-3-sulfobenzylphosphonic acid has resulted in the synthesis of two new compounds with unusual layered structures. The crystal structures of these salts and the parent acid have been determined by single crystal X-ray methods. Crystal data: 4-F-3-SO₃H-C₆H₃CH₂PO₃H₂·H₂O: triclinic, space group

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for 1519 observations (l>3σ(l)) and 182 variables; [Ni(NH₃)₂(H₂O)₄]₃(4-F-3-SO₃-C₆H₃-CH₂PO₃)₂·4H₂O: triclinic, space group

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for 2689 observations (l>3σ(I)) and 511 variables: Na₃(4-F-3-SO₃-C₆H₃CH₂PO₃)- 8.5H₂O: monoclinic, C2/c, Z = 8, A = 25.636(4), B = 6.218(4), C = 24.136(2) Å, β = 98.33(1)°, V = 3807(3) ų, R(F) = 0.047 for 2262 observations (I>2;3σ(I)) and 254 variables. The parent acid monohydrate crystallizes in layers with the acidic groups directed to the faces of the layer. The water molecules are in between the layers hydrogen-bonded to the sulfonate oxygen atoms. The nickel salt contains three independent cations, each of which is hexacoordinated to a mixture of water and ammonia molecules. Thus, there is no direct coordination of the nickel by either the sulfonate or phosphonate oxygen atoms. The structure has alternating layers, the first formed by the anions and one of the nickel complexes, and the second by the other two complexes and the free water molecules. The sodium salt also has the anions arranged in layers but with an interpenetrating three-dimensional network of ionic and hydrogen bonds involving the cations and water molecules. The sodium ions are coordinated to a mixture of sulfonate oxygen atoms and bridging water molecules in irregular six-fold environments. These structures are discussed in terms of the coordination behavior of the difunctional anions in the context of known monofunctional phosphonate and sulfonate compounds.     

Effects of Hydraulic Soil Properties on Vegetation Pattern Formation in Sloping Landscapes

Current models of vegetation pattern formation rely on a system of weakly nonlinear reaction–diffusion equations that are coupled by their source terms. While these equations, which are used to describe a spatiotemporal planar evolution of biomass and soil water, qualitatively capture the emergence of various types of vegetation patterns in arid environments, they are phenomenological and have a limited predictive power. We ameliorate these limitations by deriving the vertically averaged Richards’ equation to describe flow (as opposed to “diffusion”) of water in partially saturated soils. This establishes conditions under which this nonlinear equation reduces to its weakly nonlinear reaction–diffusion counterpart used in the previous models, thus relating their unphysical parameters (e.g., diffusion coefficient) to the measurable soil properties (e.g., hydraulic conductivity) used to parameterize the Richards equation. Our model is valid for both flat and sloping landscapes and can handle arbitrary topography and boundary conditions. The result is a model that relates the environmental conditions (e.g., precipitation rate, runoff and soil properties) to formation of multiple patterns observed in nature (such as stripes, labyrinth and spots).     

Plasma FA composition in familial LCAT deficiency indicates SOAT2-derived cholesteryl ester formation in humans

Mutations in the LCAT gene cause familial LCAT deficiency (Online Mendelian Inheritance in Man ID: #245900), a very rare metabolic disorder. LCAT is the only enzyme able to esterify cholesterol in plasma, whereas sterol O-acyltransferases 1 and 2 are the enzymes esterifying cellular cholesterol in cells. Despite the complete lack of LCAT activity, patients with familial LCAT deficiency exhibit circulating cholesteryl esters (CEs) in apoB-containing lipoproteins. To analyze the origin of these CEs, we investigated 24 carriers of LCAT deficiency in this observational study. We found that CE plasma levels were significantly reduced and highly variable among carriers of two mutant LCAT alleles (22.5 [4.0–37.8] mg/dl) and slightly reduced in heterozygotes (218 [153–234] mg/dl). FA distribution in CE (CEFA) was evaluated in whole plasma and VLDL in a subgroup of the enrolled subjects. We found enrichment of C16:0, C18:0, and C18:1 species and a depletion in C18:2 and C20:4 species in the plasma of carriers of two mutant LCAT alleles. No changes were observed in heterozygotes. Furthermore, plasma triglyceride-FA distribution was remarkably similar between carriers of LCAT deficiency and controls. CEFA distribution in VLDL essentially recapitulated that of plasma, being mainly enriched in C16:0 and C18:1, while depleted in C18:2 and C20:4. Finally, after fat loading, chylomicrons of carriers of two mutant LCAT alleles showed CEs containing mainly saturated FAs. This study of CEFA composition in a large cohort of carriers of LCAT deficiency shows that in the absence of LCAT-derived CEs, CEs present in apoB-containing lipoproteins are derived from hepatic and intestinal sterol O-acyltransferase 2.     

Zinc transporter‐1: a novel NMDA receptor‐binding protein at the postsynaptic density

Zinc (Zn²⁺) is believed to play a relevant role in the physiology and pathophysiology of the brain. Hence, Zn²⁺ homeostasis is critical and involves different classes of molecules, including Zn²⁺ transporters. The ubiquitous Zn²⁺ transporter‐1 (ZNT‐1) is a transmembrane protein that pumps cytosolic Zn²⁺ to the extracellular space, but its function in the central nervous system is not fully understood. Here, we show that ZNT‐1 interacts with GluN2A‐containing NMDA receptors, suggesting a role for this transporter at the excitatory glutamatergic synapse. First, we found that ZNT‐1 is highly expressed at the hippocampal postsynaptic density (PSD) where NMDA receptors are enriched. Two‐hybrid screening, coimmunoprecipitation experiments and clustering assay in COS‐7 cells demonstrated that ZNT‐1 specifically binds the GluN2A subunit of the NMDA receptor. GluN2A deletion mutants and pull‐down assays indicated GluN2A(1390–1464) domain as necessary for the binding to ZNT‐1. Most importantly, ZNT‐1/GluN2A complex was proved to be dynamic, since it was regulated by induction of synaptic plasticity. Finally, modulation of ZNT‐1 expression in hippocampal neurons determined a significant change in dendritic spine morphology, PSD‐95 clusters and GluN2A surface levels, supporting the involvement of ZNT‐1 in the dynamics of excitatory PSD.

     

Biochemical Origin and Refractory Properties of Humic Acid Extracted from the Maize Plant

Humic acids (HA) contribute to soil fertility because of their chemical, physical, and biological properties. The origin of HAs in soils has puzzled scientists for decades, and what HAs are and what their origin is remain unclear. The isolation of HAs in plants, which have characteristics close to soil HAs, suggests the probable origin of soil-HA is the preservation of plant tissue, indicating biochemical origin. In this paper HA from maize plant at different stages of maturity is isolated, from which it was found that the evolution of this fraction depends on and is derived from cell wall formation. Evidence was also found that HA was above all composed of lignin and cutin residues, and was characterized by low surface area. After 8 months of incubation in both mineral-artificial and natural soils, humic acid isolated form maize plant could be recovered intact.     

Virtual screening to enrich a compound collection with CDK2 inhibitors using docking, scoring, and composite scoring models

Docking programs can generate subsets of a compound collection with an increased percentage of actives against a target (enrichment) by predicting their binding mode (pose) and affinity (score), and retrieving those with the highest scores. Using the QXP and GOLD programs, we compared the ability of six single scoring functions (PLP, Ligscore, Ludi, Jain, ChemScore, PMF) and four composite scoring models (Mean Rank: MR, Rank-by-Vote: Vt, Bayesian Statistics: BS and PLS Discriminant Analysis: DA) to separate compounds that are active against CDK2 from inactives. We determined the enrichment for the entire set of actives (IC50 < 10 microM) and for three activity subsets. In all cases, the enrichment for each subset was lower than for the entire set of actives. QXP outperformed GOLD at pose prediction, but yielded only moderately better enrichments. Five to six scoring functions yielded good enrichments with GOLD poses, while typically only two worked well with QXP poses. For each program, two scoring functions generally performed better than the others (Ligscore2 and Ludi for GOLD; QXP and Jain for QXP). Composite scoring functions yielded better results than single scoring functions. The consensus approaches MR and Vt worked best when separating micromolar inhibitors from inactives. The statistical approaches BS and DA, which require training data, performed best when distinguishing between low and high nanomolar inhibitors. The key observation that all hit rate profiles for all four activity intervals for all scoring schemes for both programs are significantly better than random, is evidence that docking can be successfully applied to enrich compound collections.     

New method for selection of hydrogen peroxide adapted bifidobacteria cells using continuous culture and immobilized cell technology

Background  

Oxidative stress can severely compromise viability of bifidobacteria. Exposure of Bifidobacterium cells to oxygen causes accumulation of reactive oxygen species, mainly hydrogen peroxide, leading to cell death. In this study, we tested the suitability of continuous culture under increasing selective pressure combined with immobilized cell technology for the selection of hydrogen peroxide adapted Bifidobacterium cells. Cells of B. longum NCC2705 were immobilized in gellan-xanthan gum gel beads and used to continuously ferment MRS medium containing increasing concentration of H₂O₂ from 0 to 130 ppm.     

Intestinal gluconeogenesis is a key factor for early metabolic changes after gastric bypass but not after gastric lap-band in mice

Unlike the adjustable gastric banding procedure (AGB), Roux-en-Y gastric bypass surgery (RYGBP) in humans has an intriguing effect: a rapid and substantial control of type 2 diabetes mellitus (T2DM). We performed gastric lap-band (GLB) and entero-gastro anastomosis (EGA) procedures in C57Bl6 mice that were fed a high-fat diet. The EGA procedure specifically reduced food intake and increased insulin sensitivity as measured by endogenous glucose production. Intestinal gluconeogenesis increased after the EGA procedure, but not after gastric banding. All EGA effects were abolished in GLUT-2 knockout mice and in mice with portal vein denervation. We thus provide mechanistic evidence that the beneficial effects of the EGA procedure on food intake and glucose homeostasis involve intestinal gluconeogenesis and its detection via a GLUT-2 and hepatoportal sensor pathway.