Structural Simplification of Bedaquiline: the Discovery of 3-(4-(N,N-dimethylaminomethyl)phenyl)quinoline Derived Antitubercular Lead Compounds

Bedaquiline (BDQ) is a novel and highly potent last-line antituberculosis drug that was approved by the US FDA in 2013. Owing to its stereo-structural complexity, chemical synthesis and compound optimization are rather difficult and expensive. This study describes the structural simplification of bedaquiline while preserving antitubercular activity. The compound's structure was split into fragments and reassembled in various combinations while replacing the two chiral carbon atoms with an achiral linkage instead. Four series of analogues were designed; these candidates retained their potent antitubercular activity at sub-microgram per mL concentrations against both sensitive and multidrug-resistant (MDR) Mycobacterium tuberculosis strains. Six out of the top nine MIC-ranked candidates were found to inhibit mycobacterial ATP synthesis activity with IC50 values between 20 and 40 μm, one had IC50>66 μm, and two showed no inhibition, despite their antitubercular activity. These results provide a basis for the development of chemically less complex, lower-cost bedaquiline derivatives and describe the identification of two derivatives with antitubercular activity against non-ATP synthase related targets

Self-cleaning and antibiofouling enamel surface by slippery liquid-infused technique.

We aimed to create a slippery liquid-infused enamel surface with antibiofouling property to prevent dental biofilm/plaque formation. First, a micro/nanoporous enamel surface was obtained by 37% phosphoric acid etching. The surface was then functionalized by hydrophobic low-surface energy heptadecafluoro-1,1,2,2-tetra- hydrodecyltrichlorosilane. Subsequent infusion of fluorocarbon lubricants (Fluorinert FC-70) into the polyfluoroalkyl-silanized rough surface resulted in an enamel surface with slippery liquid-infused porous surface (SLIPS). The results of water contact angle measurement, diffuse-reflectance Fourier transform infrared spectroscopy, and atomic force microscope confirmed that the SLIPS was successfully constructed on the enamel surface. The antibiofouling property of the SLIPS was evaluated by the adsorption of salivary protein of mucin and Streptococcus mutans in vitro, as well as dental biofilm formation using a rabbit model in vivo. The results showed that the SLIPS on the enamel surface significantly inhibited mucin adhesion and S. mutans biofilm formation in vitro, and inhibited dental plaque formation in vivo.published_or_final_versio

Floral biology of Schismatoglottis baangongensis (Araceae) in West Sarawak, Borneo

The flowering mechanism, visiting insect activities, reproductive system, and floral scent composition of Schismatoglottis baangongensis a Northwest Bornean locally endemic limestone-restricted protogynous mesophyte were investigated. Anthesis started at dawn and lasted ca 29 h. Fruit set for open pollination (93 %) and restricted access pollination (88 %) were high. Colocasiomyia (Diptera, Drosophilidae) and Cycreon (Coleoptera, Hydrophilidae) were the main pollinators. Colocasiomyia flies present in much higher numbers than Cycreon beetles individually carried significantly less pollen load. Chaloenus (Chrysomelidae, Galerucinae) was inadvertent pollinators, and Atheta (Coleoptera, Staphylinidae) passive visitors. Pollen transferal between dissimilar insect genera (Colocasiomyia and Chaloenus) is reported for the first time. Low pollen/ovule ratio of S. baangongensis indicated an efficient pollination mechanism. Ester compound class floral odours, especially the dominant compounds 3-butenoic acid, 3-methyl-, methyl ester, were decisive in attracting pollinators. The spadix appendix of S. baangongensis was the main olfactory body although the spathe was detected to release an additional N-containing compound, an indole. An increase in the total amount of floral scent from the pistillate flower zone during pistillate phase of anthesis from Period I (06:00–08:00 h) to Period II (08:00–10:00 h) was postulated to detain insects in the lower chamber of the inflorescence

Transplanted Olfactory Ensheathing Cells Reduce Retinal Degeneration in Royal College of Surgeons Rats

PURPOSE OF THE STUDY: Retinitis pigmentosa (RP) is a group of genetic disorders and a slow loss of vision that is caused by a cascade of retinal degenerative events. We examined whether these retinal degenerative events were reduced after cultured mixtures of adult olfactory ensheathing cells (OECs) and olfactory nerve fibroblasts (ONFs) were transplanted into the subretinal space of 1-month-old RCS rat, a classic model of RP. MATERIALS AND METHODS: The changes in retinal photoreceptors and Müller cells of RCS rats after cell transplantation were observed by the expression of recoverin and glial fibrillary acidic protein (GFAP), counting peanut agglutinin (PNA)-positive cone outer segments and calculating the relative apoptotic area. The retinal function was also evaluated by Flash electroretinography (ERG). To further investigate the mechanisms, by which OECs/ONFs play important roles in the transplanted retinas, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and basic fibroblast growth factor (bFGF) secretion of the cultured cells were analyzed by ELISA. The ability of OECs/ONFs to ingest porcine retinal outer segments and the amount of phagocytosis were compared with retinal pigment epithelium (RPE) cells. RESULTS: Our research showed that the transplantation of OECs/ONFs mixtures restored recoverin expression, protected retinal outer segments, increased PNA-positive cone outer segments, reduced caspase-positive apoptotic figures, downregulated GFAP, and maintained the b-wave of the ERG. Cultured OECs/ONFs expressed and secreted NGF, BDNF, and bFGF which made contributions to assist survival of the photoreceptors. An in vitro phagocytosis assay showed that OECs, but not ONFs, phagocytosed porcine retinal outer segments, and the phagocytic ability of OECs was even superior to that of RPE cells. CONCLUSIONS: These findings demonstrate that transplantation of OECs/ONFs cleaned up the accumulated debris in subretinal space, and provided an intrinsic continuous supply of neurotrophic factors. It suggested that transplantation of OECs/ONFs might be a possible future route for protection of the retina and reducing retinal degeneration in RP

Interactions between 2-Cys peroxiredoxins and ascorbate in autophagosome formation during the heat stress response in Solanum lycopersicum

2-Cys peroxiredoxins (2-CPs) function in the removal of hydrogen peroxide and lipid peroxides but their precise roles in the induction of autophagy (ATG) have not been characterized. Here we show that heat stress, which is known to induce oxidative stress, leads to the simultaneous accumulation of transcripts encoding 2-CPs and ATG proteins, and also autophagosomes in tomato plants. Virus-induced gene silencing of the tomato 2-CP1, 2-CP2 and 2-CP1/2 resulted in an increased sensitivity of tomato plants to heat stress. Silencing 2-CP2 or 2-CP1/2 increased the levels of transcripts associated with ascorbate biosynthesis but had no effects on the glutathione pool in the absence of stress. However, the heat-induced accumulation of transcripts associated with the water-water cycle was compromised by the loss of 2-CP1/2 functions. The transcript levels of autophagy-related genes ATG5 and ATG7 were higher in plants with impaired 2-CP1/2 functions, and the formation of autophagosomes was increased, together with an accumulation of oxidized and insoluble proteins. Silencing of ATG5 or ATG7 increased the levels of 2-CPs transcripts and protein but decreased heat stress tolerance. These results demonstrate that 2-CPs fulfill a pivotal role in heat stress tolerance in tomato, via interactions with ascorbate-dependent pathways and autophagy

Inelastic x-ray scattering investigations of lattice dynamics in SmFeAsO1−x_{1-x}Fy_y superconductors

We report measurements of the phonon density of states as measured with inelastic x-ray scattering in SmFeAsO$_{1-x}$F$_y$ powders. An unexpected strong renormalization of phonon branches around 23 meV is observed as fluorine is substituted for oxygen. Phonon dispersion measurements on SmFeAsO$_{1-x}$F$_y$ single crystals allow us to identify the 21 meV A$_{1g}$ in-phase (Sm,As) and the 26 meV B$_{1g}$ (Fe,O) modes to be responsible for this renormalization, and may reveal unusual electron-phonon coupling through the spin channel in iron-based superconductors.Comment: 4 pages, 3 figures, submitted for SNS2010 conference proceeding

Spectrum of non-Hermitian heavy tailed random matrices

Let (X_{jk})_{j,k>=1} be i.i.d. complex random variables such that |X_{jk}| is in the domain of attraction of an alpha-stable law, with 0< alpha <2. Our main result is a heavy tailed counterpart of Girko's circular law. Namely, under some additional smoothness assumptions on the law of X_{jk}, we prove that there exists a deterministic sequence a_n ~ n^{1/alpha} and a probability measure mu_alpha on C depending only on alpha such that with probability one, the empirical distribution of the eigenvalues of the rescaled matrix a_n^{-1} (X_{jk})_{1<=j,k<=n} converges weakly to mu_alpha as n tends to infinity. Our approach combines Aldous & Steele's objective method with Girko's Hermitization using logarithmic potentials. The underlying limiting object is defined on a bipartized version of Aldous' Poisson Weighted Infinite Tree. Recursive relations on the tree provide some properties of mu_alpha. In contrast with the Hermitian case, we find that mu_alpha is not heavy tailed.Comment: Expanded version of a paper published in Communications in Mathematical Physics 307, 513-560 (2011

Collective Modes and the Superconducting State Spectral Function of Bi2212

Photoemission spectra of the high temperature superconductor Bi2212 near (pi,0) show a dramatic change when cooling below Tc: the broad peak in the normal state turns into a sharp low energy peak followed by a higher binding energy hump. Recent experiments find that this low energy peak persists over a significant range in momentum space. We show in this paper that these data are well described by a simple model of electrons interacting with a collective mode which appears only below Tc.Comment: 4 pages, revtex, 4 encapsulated postscript figure

Direct Simulation of a Solidification Benchmark Experiment

International audienceA solidification benchmark experiment is simulated using a three-dimensional cellular automaton-finite element solidification model. The experiment consists of a rectangular cavity containing a Sn-3 wt pct Pb alloy. The alloy is first melted and then solidified in the cavity. A dense array of thermocouples permits monitoring of temperatures in the cavity and in the heat exchangers surrounding the cavity. After solidification, the grain structure is revealed by metallography. X-ray radiography and inductively coupled plasma spectrometry are also conducted to access a distribution map of Pb, or macrosegregation map. The solidification model consists of solutions for heat, solute mass, and momentum conservations using the finite element method. It is coupled with a description of the development of grain structure using the cellular automaton method. A careful and direct comparison with experimental results is possible thanks to boundary conditions deduced from the temperature measurements, as well as a careful choice of the values of the material properties for simulation. Results show that the temperature maps and the macrosegregation map can only be approached with a three-dimensional simulation that includes the description of the grain structure

The connection between superconducting phase correlations and spin excitations in YBa2_2Cu3_3O6.6_{6.6}: A magnetic field study

One of the most striking universal properties of the high-transition-temperature (high-$T_c$) superconductors is that they are all derived from the hole-doping of their insulating antiferromagnetic (AF) parent compounds. From the outset, the intimate relationship between magnetism and superconductivity in these copper-oxides has intrigued researchers. Evidence for this link comes from neutron scattering experiments that show the unambiguous presence of short-range AF correlations (excitations) in cuprate superconductors. Even so, the role of such excitations in the pairing mechanism and superconductivity is still a subject of controversy. For YBa$_2$Cu$_3$O$_{6+x}$, where $x$ controls the hole-doping level, the most prominent feature in the magnetic excitations spectra is the ``resonance''. Here we show that for underdoped YBa$_2$Cu$_3$O$_{6.6}$, where $x$ and $T_c$ are below the optimal values, modest magnetic fields suppress the resonance significantly, much more so for fields approximately perpendicular rather than parallel to the CuO$_2$ planes. Our results indicate that the resonance measures pairing and phase coherence, suggesting that magnetism plays an important role in the superconductivity of cuprates. The persistence of a field effect above $T_c$ favors mechanisms with preformed pairs in the normal state of underdoped cuprates.Comment: 12 pages, 4 figures, Nature (in press