Changes of the phagosomal elemental concentrations by Mycobacterium tuberculosis Mramp

Pathogenic mycobacteria survive within phagosomes which are thought to represent a nutrient-restricted environment. Divalent cation transporters of the Nramp family in phagosomes and mycobacteria (Mramp) may compete for metals that are crucial for bacterial survival. The elemental concentrations in phagosomes of macrophages infected with wild-type Mycobacterium tuberculosis (M. tuberculosis strain H37Rv) and a M. tuberculosis Mramp knockout mutant (Mramp-KO), derived from a clinical isolate isogenic to the strain MT103, were compared. Time points of 1 and 24 h after infection of mouse peritoneal macrophages (bcgS) were compared in both cases. Increased concentrations of P, Ni and Zn and reduced Cl concentration in Mramp-KO after 1 h of infection were observed, compared to M. tuberculosis vacuoles. After 24 h of infection, significant differences in the P, Cl and Zn concentrations were still present. The Mramp-KO phagosome showed a significant increase of P, Ca, Mn, Fe and Zn concentrations between 1 and 24 h after infection, while the concentrations of K and Ni decreased. In the M. tuberculosis vacuole, the Fe concentration showed a similar increase, while the Cl concentration decreased. The fact that the concentration of several divalent cations increased in the Mramp-KO strain suggests that Mramp may have no impact on the import of these divalent cations into the mycobacterium, but may function as a cation efflux pump. The concordant increase of Fe concentrations within M. tuberculosis, as well as within the Mramp-KO vacuoles, implies that Mramp, in contrast to siderophores, might not be important for the attraction of Fe and its retention in phagosomes of unstimulated macrophages

Percolation Transition in the random antiferromagnetic spin-1 chain

We give a physical description in terms of percolation theory of the phase transition that occurs when the disorder increases in the random antiferromagnetic spin-1 chain between a gapless phase with topological order and a random singlet phase. We study the statistical properties of the percolation clusters by numerical simulations, and we compute exact exponents characterizing the transition by a real-space renormalization group calculation.Comment: 9 pages, 4 encapsulated Postscript figures, REVTeX 3.

The Use of Zidovudine Pharmacophore in Multi-Target-Directed Ligands for AIDS Therapy

The concept of polypharmacology embraces multiple drugs combined in a therapeutic regimen (drug combination or cocktail), fixed dose combinations (FDCs), and a single drug that binds to different targets (multi-target drug). A polypharmacology approach is widely applied in the treatment of acquired immunodeficiency syndrome (AIDS), providing life-saving therapies for millions of people living with HIV. Despite the success in viral load suppression and patient survival of combined antiretroviral therapy (cART), the development of new drugs has become imperative, owing to the emergence of resistant strains and poor adherence to cART. 3′-azido-2′,3′-dideoxythymidine, also known as azidothymidine or zidovudine (AZT), is a widely applied starting scaffold in the search for new compounds, due to its good antiretroviral activity. Through the medicinal chemistry tool of molecular hybridization, AZT has been included in the structure of several compounds allowing for the development of multi-target-directed ligands (MTDLs) as antiretrovirals. This review aims to systematically explore and critically discuss AZT-based compounds as potential MTDLs for the treatment of AIDS. The review findings allowed us to conclude that: (i) AZT hybrids are still worth exploring, as they may provide highly active compounds targeting different steps of the HIV-1 replication cycle; (ii) AZT is a good starting point for the preparation of co-drugs with enhanced cell permeability

Random bond Ising chain in a transverse magnetic field: A finite-size scaling analysis

We investigate the zero-temperature quantum phase transition of the random bond Ising chain in a transverse magnetic field. Its critical properties are identical to those of the McCoy-Wu model, which is a classical Ising model in two dimensions with layered disorder. The latter is studied via Monte Carlo simulations and transfer matrix calculations and the critical exponents are determined with a finite-size scaling analysis. The magnetization and susceptibility obey conventional rather than activated scaling. We observe that the order parameter-- and correlation function--probability distribution show a nontrivial scaling near the critical point which implies a hierarchy of critical exponents associated with the critical behavior of the generalized correlation lengths.Comment: RevTeX 13 pages + 4 figures (appended as uuencoded compressed tar-file), THP61-9

High-field MR imaging in pediatric congenital heart disease: Initial results

BackgroundComprehensive assessment of pediatric congenital heart disease (CHD) at any field strength mandates evaluation of both vascular and dynamic cardiac anatomy for which diagnostic quality contrast-enhanced magnetic resonance angiography (CEMRA) and cardiac cine are crucial.ObjectiveTo determine whether high-resolution (HR) CEMRA and steady-state free precession (SSFP) cine can be performed reliably at 3.0 T in children with CHD and to compare the image quality to similar techniques performed at 1.5 T.Materials and methodsTwenty-eight patients with a median age of 5 months and average weight 9.0 ± 7.8 kg with suspected or known CHD were evaluated at 3.0 T. SSFP cine (n = 86 series) and HR-CEMRA (n = 414 named vascular segments) were performed and images were scored for image quality and artifacts. The findings were compared to those of 28 patients with CHD of similar weight who were evaluated at 1.5 T.ResultsOverall image quality on HR-CEMRA was rated as excellent or good in 96% (397/414) of vascular segments at 3.0 T (k = 0.49) and in 94% (349/371) of vascular segments at 1.5 T (k = 0.36). Overall image quality of SSFP was rated excellent or good in 91% (78/86) of cine series at 3.0 T (k = 0.55) and in 81% (87/108) at 1.5 T (k = 0.47). Off-resonance artifact was common at both field strengths, varied over the cardiac cycle and was more prevalent at 3.0 T. At 3.0 T, off-resonance dark band artifact on SSFP cine was absent in 3% (3/86), mild in 69% (59/86), moderate in 27% (23/86) and severe in 1% (1/86) of images; at 1.5 T, dark band artifact was absent in 16% (17/108), mild in 69% (75/108), moderate in 12% (13/108) and severe in 3% (3/108) of cine images. The signal-to-noise ratio and contrast-to-noise ratio of both SSFP cine and HR-CEMRA images were significantly higher at 3.0 T than at 1.5 T (P < 0.001).ConclusionSignal-to-noise ratio and contrast-to-noise ratio of high-resolution contrast-enhanced magnetic resonance angiography and SSFP cine were higher at 3.0 T than at 1.5 T. Artifacts on SSFP cine were cardiac phase specific and more prevalent at 3.0 T such that frequency-tuning was required in one-third of exams. In neonates, high spatial resolution CEMRA was highly reliable in defining extracardiac vascular anatomy

Density Matrix Renormalization Group Study of the Haldane Phase in Random One-Dimensional Antiferromagnets

It is conjectured that the Haldane phase of the S=1 antiferromagnetic Heisenberg chain and the $S=1/2$ ferromagnetic-antiferromagnetic alternating Heisenberg chain is stable against any strength of randomness, because of imposed breakdown of translational symmetry. This conjecture is confirmed by the density matrix renormalization group calculation of the string order parameter and the energy gap distribution.Comment: 4 Pages, 7 figures; Considerable revisions are made in abstract and main text. Final accepted versio

Rapid Suppression of the Spin Gap in Zn-doped CuGeO_3 and SrCu_2O_3

The influence of non-magnetic impurities on the spectrum and dynamical spin structure factor of a model for CuGeO$_3$ is studied. A simple extension to Zn-doped ${\rm Sr Cu_2 O_3}$ is also discussed. Using Exact Diagonalization techniques and intuitive arguments we show that Zn-doping introduces states in the Spin-Peierls gap of CuGeO$_3$. This effect can beunderstood easily in the large dimerization limit where doping by Zn creates ``loose'' S=1/2 spins, which interact with each other through very weak effective antiferromagnetic couplings. When the dimerization is small, a similar effect is observed but now with the free S=1/2 spins being the resulting S=1/2 ground state of severed chains with an odd number of sites. Experimental consequences of these results are discussed. It is interesting to observe that the spin correlations along the chains are enhanced by Zn-doping according to the numerical data presented here. As recent numerical calculations have shown, similar arguments apply to ladders with non-magnetic impurities simply replacing the tendency to dimerization in CuGeO$_3$ by the tendency to form spin-singlets along the rungs in SrCu$_2$O$_3$.Comment: 7 pages, 8 postscript figures, revtex, addition of figure 8 and a section with experimental predictions, submmited to Phys. Rev. B in May 199

Quantum Spin Glasses

Ising spin glasses in a transverse field exhibit a zero temperature quantum phase transition, which is driven by quantum rather than thermal fluctuations. They constitute a universality class that is significantly different from the classical, thermal phase transitions. Most interestingly close to the transition in finite dimensions a quantum Griffiths phase leads to drastic consequences for various physical quantities: for instance diverging magnetic susceptibilities are observable over a whole range of transverse field values in the disordered phase.Comment: 10 pages LaTeX (Springer Lecture Notes style file included), 1 eps-figure; Review article for XIV Sitges Conference: Complex Behavior of Glassy System