A comparative phase 1 clinical trial to identify anti-infective mechanisms of vitamin D in people with HIV infection

Objectives:To determine if there is a biological mechanism that explains the association between HIV disease progression and increased mortality with low circulating vitamin D levels; specifically, to determine if restoring vitamin D levels induced T-cell functional changes important for antiviral immunity.Design:This was a pilot, open-label, three-arm prospective phase 1 study.Methods:We recruited 28 patients with low plasma vitamin D (<50nmol/l 25-hydroxyvitamin D3), comprising 17 HIV+ patients (11 on HAART, six treatment-naive) and 11 healthy controls, who received a single dose of 200000IU oral cholecalciferol. Advanced T-cell flow cytometry methods measured CD4(+) T-cell function associated with viral control in blood samples at baseline and 1-month after vitamin D supplementation.Results:One month of vitamin D supplementation restored plasma levels to sufficiency (>75nmol/l) in 27 of 28 patients, with no safety issues. The most striking change was in HIV+ HAART+ patients, where increased frequencies of antigen-specific T cells expressing macrophage inflammatory protein (MIP)-1 - an important anti-HIV blocking chemokine - were observed, with a concomitant increase in plasma MIP-1, both of which correlated significantly with vitamin D levels. In addition, plasma cathelicidin - a vitamin D response gene with broad antimicrobial activity - was enhanced.Conclusion:Vitamin D supplementation modulates disease-relevant T-cell functions in HIV-infected patients, and may represent a useful adjunct to HAART therapy. Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved.

Tyrosine kinases and calcium dependent activation of endothelial cell phospholipase D by diperoxovanadate

Reactive oxygen species (ROS) mediated modulation of signal transduction pathways represent an important mechanism of cell injury and barrier dysfunction leading to the development of vascular disorders. Towards understanding the role of ROS in vascular dysfunction, we investigated the effect of diperoxovanadate (DPV), derived from mixing hydrogen peroxide and vanadate, on the activation of phospholipase D (PLD) in bovine pulmonary artery endothelial cells (BPAECs). Addition of DPV to BPAECs in the presence of .05% butanol resulted in an accumulation of [P-32] phosphatidylbutanol (PBt) in a dose- and time-dependent manner. DPV also caused an increase in tyrosine phosphorylation of several protein bands (Mr 20-200 kD), as determined by Western blot analysis with antiphosphotyrosine antibodies. The DPV-induced [P-32] PBt-accumulation was inhibited by putative tyrosine kinase inhibitors such as genistein, herbimycin, tyrphostin and by chelation of Ca2+ with either EGTA or BAPTA, however, pretreatment of BPAECs with the inhibitor PKC bisindolylmaleimide showed minimal inhibition. Also down-regulation of PKC alpha and epsilon, the major isotypes of PKC in BPAECs, by TPA (100 nM, 18 h) did not attenuate the DPV-induced PLD activation. The effects of putative tyrosine kinase and PKC inhibitors were specific as determined by comparing [P-32] PBt formation between DPV and TPA. In addition to tyrosine kinase inhibitors, antioxidants such as N-acetylcysteine and pyrrolidine dithiocarbamate also attenuated DPV-induced protein tyrosine phosphorylation and PLD stimulation. These results suggest that oxidation, prevented by reduction with thiol compounds, is involved in DPV-dependent protein tyrosine phosphorylation and PLD activation.

Effect of spatial dispersion of the dielectric on the binding energy of D- ion in Si and Ge

Using a multivalley effective mass theory, we obtain the binding energy of a D- ion in Si and Ge taking into account the spatial variation of the host dielectric function. We find that on comparison with experimental results the effect of spatial dispersion is important in the estimation of binding energy for the D- formed by As in Si and Ge. The effect is less significant for the case of D- formed by P and Sb donors.

D.c. and a.c. polarographic behaviour of vanadium-glycine complexes

A detailed investigation of the d.c. polarographic behaviour of vanadium(V),-(IV) and -(III) in glycine solutions has been made keeping the total glycine concentration at 0.1, 0.5 and 1.0 M and varying the pH of the solution. Experiments keeping the pH constant (using different ratios of glycine and glycine anion) and varying the glycine anion concentration, and also in predominantly anion solutions, have been made.

d-Regular Graphs of Acyclic Chromatic Index at Least d+2

An acyclic edge coloring of a graph is a proper edge coloring such that there are no bichromatic cycles. The acyclic chromatic index of a graph is the minimum number k such that there is an acyclic edge coloring using k colors and is denoted by a'(G). It was conjectured by Alon, Suclakov and Zaks (and earlier by Fiamcik) that a'(G) <= Delta+2, where Delta = Delta(G) denotes the maximum degree of the graph. Alon et al. also raised the question whether the complete graphs of even order are the only regular graphs which require Delta+2 colors to be acyclically edge colored. In this article, using a simple counting argument we observe not only that this is not true, but in fact all d-regular graphs with 2n vertices and d&gt;n, requires at least d+2 colors. We also show that a'(K-n,K-n) >= n+2, when n is odd using a more non-trivial argument. (Here K-n,K-n denotes the complete bipartite graph with n vertices on each side.) This lower bound for Kn,n can be shown to be tight for some families of complete bipartite graphs and for small values of n. We also infer that for every d, n such that d >= 5, n >= 2d+3 and dn even, there exist d-regular graphs which require at least d+2-colors to be acyclically edge colored. (C) 2009 Wiley Periodicals, Inc. J Graph Theory 63: 226-230, 2010.

Effect of substituent on the thermodynamics of D-glucopyranoside binding to concanavalin A, pea (Pisum sativum) lectin and lentil (Lens culinaris) lectin

Titration calorimetry measurements of the binding of phenyl-alpha (alpha PhOGlu), 3-methoxy (3MeOGlu), fluorodeoxy and deoxy derivatives of alpha-D-glucopyranose (Glu) to concanavalin A (conA), pea lectin and lentil lectin were performed at approx. 10 and 25 degrees C in 0.01 M dimethylglutaric acid/NaOH buffer, pH 6.9, containing 0.15 M NaCl and Mn2+ and Ca2+ ions. Apparently the 3-deoxy, 4-deoxy and 6-deoxy as well as the 4-fluorodeoxy and 6-fluorodeoxy derivatives of Glu do not bind to the lectins because no heat release was observed on the addition of aliquots of solutions of these derivatives to the lectin solutions. The binding enthalpies, delta H0b, and entropies, delta S0b, determined from the measurements were compared with the same thermodynamic binding parameters for Glu, D-mannopyranoside and methyl-alpha- D-glucopyranoside (alpha MeOGlu). The binding reactions are enthalpically driven with little change in the heat capacity on binding, and exhibit enthalpy-entropy compensation. Differences between the thermodynamic binding parameters can be rationalized in terms of the interactions apparent in the known crystal structures of the methyl-alpha-D-mannopyranoside-conA [Derewenda, Yariv, Helliwell, Kalb (Gilboa), Dodson, Papiz, Wan and Campbell (1989) EMBO J. 8, 2189-2193] and pea lectin-trimanno-pyranoside [Rini, Hardman, Einspahr, Suddath and Carber (1993) J. Biol. Chem. 268, 10126-10132] complexes. Increases in the entropy change on binding are observed for alpha MeOGlu binding to pea and lentil lectin, for alpha PhOGlu binding to conA and pea lectin, and for 3MeOGlu binding to pea lectin relative to the entropy change for Glu binding, and imply that the phenoxy and methoxy substituents provide additional hydrophobic interactions in the complex. Increases in the binding enthalpy relative to that of Glu are observed for deoxy and fluoro derivatives in the C-1 and C-2 positions and imply that these substituents weaken the interaction with the surrounding water, thereby strengthening the interaction with the binding site.

Interaction between the Z-type DNA duplex and 1,3-propanediamine:crystal structure of d(CACGTG)(2) at 1.2 angstrom resolution

The crystal structure of a hexamer duplex d(CACGTG)(2) has been determined and refined to an R-factor of 18.3% using X-ray data up to 1.2 angstrom resolution. The sequence crystallizes as a left-handed Z-form double helix with Watson-Crick base pairing. There is one hexamer duplex, a spermine molecule, 71 water molecules, and an unexpected diamine (Z-5, 1,3-propanediamine, C3H10N2)) in the asymmetric unit. This is the high-resolution non-disordered structure of a Z-DNA hexamer containing two AT base pairs in the interior of a duplex with no modifications such as bromination or methylation on cytosine bases. This structure does not possess multivalent cations such as cobalt hexaammine that are known to stabilize Z-DNA. The overall duplex structure and its crystal interactions are similar to those of the pure-spermine form of the d(CGCGCG)(2) structure. The spine of hydration in the minor groove is intact except in the vicinity of the T5A8 base pair. The binding of the Z-5 molecule in the minor grove of the d(CACGTG)(2) duplex appears to have a profound effect in conferring stability to a Z-DNA conformation via electrostatic complementarity and hydrogen bonding interactions. The successive base stacking geometry in d(CACGTG)(2) is similar to the corresponding steps in d(CG)(3). These results suggest that specific polyamines such as Z-5 could serve as powerful inducers of Z-type conformation in unmodified DNA sequences with AT base pairs. This structure provides a molecular basis for stabilizing AT base pairs incorporated into an alternating d(CG) sequence.

On Walkup's class K (d) and a minimal triangulation of (S-3 (sic) S-1)(#3)

For d >= 2, Walkup's class K (d) consists of the d-dimensional simplicial complexes all whose vertex-links are stacked (d - 1)-spheres. Kalai showed that for d >= 4, all connected members of K (d) are obtained from stacked d-spheres by finitely many elementary handle additions. According to a result of Walkup, the face vector of any triangulated 4-manifold X with Euler characteristic chi satisfies f(1) >= 5f(0) - 15/2 chi, with equality only for X is an element of K(4). Kuhnel observed that this implies f(0)(f(0) - 11) >= -15 chi, with equality only for 2-neighborly members of K(4). Kuhnel also asked if there is a triangulated 4-manifold with f(0) = 15, chi = -4 (attaining equality in his lower bound). In this paper, guided by Kalai's theorem, we show that indeed there is such a triangulation. It triangulates the connected sum of three copies of the twisted sphere product S-3 (sic) S-1. Because of Kuhnel's inequality, the given triangulation of this manifold is a vertex-minimal triangulation. By a recent result of Effenberger, the triangulation constructed here is tight. Apart from the neighborly 2-manifolds and the infinite family of (2d + 3)-vertex sphere products Sd-1 X S-1 (twisted for d odd), only fourteen tight triangulated manifolds were known so far. The present construction yields a new member of this sporadic family. We also present a self-contained proof of Kalai's result. (C) 2011 Elsevier B.V. All rights reserved.

A new class of three dimensional D-pi-A trigonal cryptand derivatives for second-order nonlinear optics

Synthesis, crystal structures, linear and nonlinear optical properties of tris D-pi-A cryptand derivatives with C-3 symmetry are reported. Three fold symmetry inherent in the cryptand molecules has been utilized for designing these molecules. Molecular nonlinearities have been measured by hyper-Rayleigh scattering (HRS) experiments. Among the compounds studied, L-1 adopts non-centrosymmetric crystal structure. Compounds L-1, L-2, L-3 and L-4 show a measurable SHG powder signal. These molecules are more isotropic and have significantly higher melting points than the classical p-nitroaniline based dipolar NLO compounds, making them useful for further device applications. Besides, different acceptor groups can be attached to the cryptand molecules to modulate their NLO properties.

Synthesis of 5-p-hydroxybenzyl-5,6-dihydro-2-naphthol, (+/-)-sequirin-d

A high-yield six-step synthesis of sequirin D (1a), a naturally occurring norlignan, is described. Michael addition of deoxyanisoin (2) to acrylonitrile gives a ketonitrile (3), which on Wolff–Kishner reduction is reduced and hyrolysed in situ to 4,5-bis-p-methoxyphenylpentanoic acid (4). Cyclodehydration of (4) with polyphosphoric acid, followed by borohydride reduction and dehydration furnishes di-O-methylsequirin D (1b) which affords on demethylation sequirin D (1a) in an overall yield from (2) of 60%. The key synthon (4) has also been prepared by three other routes.

A multichannel sampling method for 2-D finite-rate-of-innovation signals

We address the problem of sampling and reconstruction of two-dimensional (2-D) finite-rate-of-innovation (FRI) signals. We propose a three-channel sampling method for efficiently solving the problem. We consider the sampling of a stream of 2-D Dirac impulses and a sum of 2-D unit-step functions. We propose a 2-D causal exponential function as the sampling kernel. By causality in 2-D, we mean that the function has its support restricted to the first quadrant. The advantage of using a multichannel sampling method with causal exponential sampling kernel is that standard annihilating filter or root-finding algorithms are not required. Further, the proposed method has inexpensive hardware implementation and is numerically stable as the number of Dirac impulses increases.

On linear series and a conjecture of D. C. Butler

Let C be a smooth irreducible projective curve of genus g and L a line bundle of degree d generated by a linear subspace V of H-0 (L) of dimension n+1. We prove a conjecture of D. C. Butler on the semistability of the kernel of the evaluation map V circle times O-C -> L and obtain new results on the stability of this kernel. The natural context for this problem is the theory of coherent systems on curves and our techniques involve wall crossing formulae in this theory.

Adaptive Mesh Refinement for Fast Convergence of EFIE-Based 3-D Extraction

3-D full-wave method of moments (MoM) based electromagnetic analysis is a popular means toward accurate solution of Maxwell's equations. The time and memory bottlenecks associated with such a solution have been addressed over the last two decades by linear complexity fast solver algorithms. However, the accurate solution of 3-D full-wave MoM on an arbitrary mesh of a package-board structure does not guarantee accuracy, since the discretization may not be fine enough to capture spatial changes in the solution variable. At the same time, uniform over-meshing on the entire structure generates a large number of solution variables and therefore requires an unnecessarily large matrix solution. In this paper, different refinement criteria are studied in an adaptive mesh refinement platform. Consequently, the most suitable conductor mesh refinement criterion for MoM-based electromagnetic package-board extraction is identified and the advantages of this adaptive strategy are demonstrated from both accuracy and speed perspectives. The results are also compared with those of the recently reported integral equation-based h-refinement strategy. Finally, a new methodology to expedite each adaptive refinement pass is proposed.

Enhancement of nonvolatile polarization and pyroelectric sensitivity in lithium tantalate (LT)/poly(vinylidene fluoride) (PVDF) nanocomposite

We report the ferroelectric and pyroelectric properties of the composite films of lithium tantalate (LT) nanoparticle in poly(vinylidene fluoride) PVDF matrix at different volume fractions of LT (f(LT) = 0.047, 0.09 and 0.17). For an applied electric field of 150 kV cm(-1) the nonvolatile polarization of the composite was observed to increase from 0.014 mu C cm(-2) at f(LT) = 0 to 2.06 mu C cm(-2) at f(LT) = 0.17. For f(LT) = 0.17, the composite films exhibit a saturated ferroelectric hysteresis loop with a remanent polarization (2P(r) = 4.13 mu C cm(-2)). Compared with pure poled PVDF the composite films also showed a factor of about five enhancement in the pyroelectric coefficient at f(LT) = 0.17. When used in energy detection mode the pyroelectric voltage sensitivity of the composite films was found to increase from 3.93 to 18.5 VJ(-1) with an increase in f(LT) from 0.0 to 0.17.

Magnetization, magnetotransport and electron magnetic resonance studies of nanoparticles and nanowires of Pr0.5Sr0.5MnO3

In this paper, we present the preparation and characterization of nanoparticles and nanowires of Pr0.5Sr0.5MnO3 (PSMO). The main results of this investigation are as follows: (a) a comparison with the properties of the bulk material shows that the ferromagnetic (FM) transition at 270 K remains unaffected but the anti-ferromagnetic (AFM) transition at TN = 150 K disappears in the nanoparticles, (b) the size induced ground state magnetic phase (below 150 K) is predominantly FM, coexisting with a residual AFM phase, and (c) the temperature dependence of magnetic anisotropy shows complex behaviour, being higher in the nanoparticles at high temperatures and lower at moderately lower temperatures in comparison with the bulk. The results obtained from the extensive magnetization, magnetotransport and electron magnetic resonance studies made on various samples are presented and discussed in detail.