Exploring the active site of the Streptococcus pneumoniae topoisomerase IV-DNA cleavage complex with novel 7,8-bridged fluoroquinolones.

As part of a programme of synthesizing and investigating the biological properties of new fluoroquinolone antibacterials and their targeting of topoisomerase IV from Streptococcus pneumoniae, we have solved the X-ray structure of the complexes of two new 7,8-bridged fluoroquinolones (with restricted C7 group rotation favouring tight binding) in complex with the topoisomerase IV from S. pneumoniae and an 18-base-pair DNA binding site-the E-site-found by our DNA mapping studies to bind drug strongly in the presence of topoisomerase IV (Leo et al. 2005 J. Biol. Chem. 280, 14 252-14 263, doi:10.1074/jbc.M500156200). Although the degree of antibiotic resistance towards fluoroquinolones is much lower than that of β-lactams and a range of ribosome-bound antibiotics, there is a pressing need to increase the diversity of members of this successful clinically used class of drugs. The quinolone moiety of the new 7,8-bridged agents ACHN-245 and ACHN-454 binds similarly to that of clinafloxocin, levofloxacin, moxifloxacin and trovofloxacin but the cyclic scaffold offers the possibility of chemical modification to produce interactions with other topoisomerase residues at the active site

Weak localization of Dirac fermions in graphene beyond the diffusion regime

We develop a microscopic theory of the weak localization of two-dimensional massless Dirac fermions which is valid in the whole range of classically weak magnetic fields. The theory is applied to calculate magnetoresistance caused by the weak localization in graphene and conducting surfaces of bulk topological insulators.Comment: 5 pages, 2 figure

The CP violating phase γ\gamma from global fit of rare charmless hadronic B decays

We study constraints on the CP violating phase $\gamma$ in the Kobayashi-Maskawa model using available experimental data. We first follow the conventional method to up date the constraint on $\gamma$ by performing a $\chi^2$ analysis using data from $|\epsilon_K|$, $\Delta m_{B_{d,s}}$ and $|V_{ub}/V_{cb}|$. We also include the recent information on $\sin2\beta$ in the analysis. We obtain the best fit for $\gamma$ to be $66^\circ$ and the 95% C.L. allowed range to be $42^\circ \sim 87^\circ$. We then develop a method to carry out a $\chi^2$ analysis based on SU(3) symmetry using data from $B\to \pi \pi$ and $B\to K \pi$. We also discuss SU(3) breaking effects from model estimate. We find that present data on $B\to \pi\pi, K \pi$ can also give some constraint on $\gamma$ although weaker than the earlier method limited by the present experimental errors. Future improved data will provide more stringent constraint. Finally we perform a combined fit using data from $|\epsilon_K|$, $\Delta m_{B_{d,s}}$, $|V_{ub}/V_{cb}|$, $\sin2\beta$ and rare charmless hadronic B decays. The combined analysis gives $\gamma=67^\circ$ for the best fit value and $43^\circ \sim 87^\circ$ as the 95% C.L. allowed range. Several comments on other methods to determine $\gamma$ based on SU(3) symmetry are also provided.Comment: Revised verion with the new experimental data from Belle and Babar included in the analysis to obtain the global fit for the CP violating phase gamma. RevTex, 32 pages and 8 figure

Lack of Airborne Transmission during Outbreak of Pandemic (H1N1) 2009 among Tour Group Members, China, June 2009

This outbreak was caused by droplet transmission

Low cross-talk optical addressing of trapped-ion qubits using a novel integrated photonic chip

Individual optical addressing in chains of trapped atomic ions requires the generation of many small, closely spaced beams with low cross-talk. Furthermore, implementing parallel operations necessitates phase, frequency, and amplitude control of each individual beam. Here, we present a scalable method for achieving all of these capabilities using a high-performance integrated photonic chip coupled to a network of optical fibre components. The chip design results in very low cross-talk between neighbouring channels even at the micrometre-scale spacing by implementing a very high refractive index contrast between the channel core and cladding. Furthermore, the photonic chip manufacturing procedure is highly flexible, allowing for the creation of devices with an arbitrary number of channels as well as non-uniform channel spacing at the chip output. We present the system used to integrate the chip within our ion trap apparatus and characterise the performance of the full individual addressing setup using a single trapped ion as a light-field sensor. Our measurements showed intensity cross-talk below ~10–3 across the chip, with minimum observed cross-talk as low as ~10–5

Adeno-Associated Virus Neutralizing Antibodies in Large Animals and Their Impact on Brain Intraparenchymal Gene Transfer

Pre-existing neutralizing antibody (NAb) against adeno-associated virus (AAV) commonly found in primates is a major host barrier that can severely compromise in vivo gene transfer by AAV vectors. To achieve proof-of-concept success in clinical development of recombinant AAV (rAAV)-based in vivo gene therapy, it is crucial to consider the potential interference of NAb and to enroll serologically compatible study subjects. In this study, we report a large AAV NAb dataset comprising multiple large animal species and AAV serotypes and compare two NAb assays based on in vitro or in vivo transduction inhibition, respectively. Together with previously published AAV seroepidemiology studies, these data can serve as a reference for selecting suitable serotypes, study subjects of large animal species, and potentially human patients for rAAV treatment. In addition, we modeled the intrathalamus rAAV9 delivery in the presence of circulating anti-AAV9 NAb generated by either pre-immunization or passive transfer of NAb-positive large animal serum to mice. The data showed that circulating NAb may not be the sole determinant to inhibit braintransduction. Other aspects of pre-existing AAV immunity following natural infection or rAAV administration may be further studied to establish a more accurate inclusion criterion for clinical studies employing intraparenchymal rAAV9 injections

On-chip beam rotators, polarizers and adiabatic mode converters through low-loss waveguides with variable cross-sections

Photonics integrated circuitry would benefit considerably from the ability to arbitrarily control waveguide cross-sections with high precision and low loss, in order to provide more degrees of freedom in manipulating propagating light. Here, we report on a new optical-fibres-compatible glass waveguide by femtosecond laser writing, namely spherical phase induced multi-core waveguide (SPIM-WG), which addresses this challenging task with three dimensional on-chip light control. Precise deformation of cross-sections is achievable along the waveguide, with shapes and sizes finely controllable of high resolution in both horizontal and vertical transversal directions. We observed that these waveguides have high refractive index contrast of 0.017, low propagation loss of 0.14 dB/cm, and very low coupling loss of 0.19 dB coupled from a single mode fibre. SPIM-WG devices were easily fabricated that were able to perform on-chip beam rotation through varying angles, or manipulate polarization state of propagating light for target wavelengths. We also demonstrated SPIM-WG mode converters that provide arbitrary adiabatic mode conversion with high efficiency between symmetric and asymmetric non-uniform modes; examples include circular, elliptical modes and asymmetric modes from ppKTP waveguides which are generally applied in frequency conversion and quantum light sources. Created inside optical glass, these waveguides and devices have the capability to operate across ultra-broad bands from visible to infrared wavelengths. The compatibility with optical fibre also paves the way toward packaged photonic integrated circuitry, which usually needs input and output fibre connections

Mechanical properties of freely suspended atomically thin dielectric layers of mica

We have studied the elastic deformation of freely suspended atomically thin sheets of muscovite mica, a widely used electrical insulator in its bulk form. Using an atomic force microscope, we carried out bending test experiments to determine the Young's modulus and the initial pre-tension of mica nanosheets with thicknesses ranging from 14 layers down to just one bilayer. We found that their Young's modulus is high (190 GPa), in agreement with the bulk value, which indicates that the exfoliation procedure employed to fabricate these nanolayers does not introduce a noticeable amount of defects. Additionally, ultrathin mica shows low pre-strain and can withstand reversible deformations up to tens of nanometers without breaking. The low pre-tension and high Young's modulus and breaking force found in these ultrathin mica layers demonstrates their prospective use as a complement for graphene in applications requiring flexible insulating materials or as reinforcement in nanocomposites.Comment: 9 pages, 5 figures, selected as cover of Nano Research, Volume 5, Number 8 (2012

The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress

The MRE11/RAD50/NBS1 (MRN) complex is a major sensor of DNA double strand breaks, whose role in controlling faithful DNA replication and preventing replication stress is also emerging. Inactivation of the MRN complex invariably leads to developmental and/or degenerative neuronal defects, the pathogenesis of which still remains poorly understood. In particular, NBS1 gene mutations are associated with microcephaly and strongly impaired cerebellar development, both in humans and in the mouse model. These phenotypes strikingly overlap those induced by inactivation of MYCN, an essential promoter of the expansion of neuronal stem and progenitor cells, suggesting that MYCN and the MRN complex might be connected on a unique pathway essential for the safe expansion of neuronal cells. Here, we show that MYCN transcriptionally controls the expression of each component of the MRN complex. By genetic and pharmacological inhibition of the MRN complex in a MYCN overexpression model and in the more physiological context of the Hedgehog-dependent expansion of primary cerebellar granule progenitor cells, we also show that the MRN complex is required for MYCN-dependent proliferation. Indeed, its inhibition resulted in DNA damage, activation of a DNA damage response, and cell death in a MYCN- and replication-dependent manner. Our data indicate the MRN complex is essential to restrain MYCN-induced replication stress during neural cell proliferation and support the hypothesis that replication-born DNA damage is responsible for the neuronal defects associated with MRN dysfunctions.Cell Death and Differentiation advance online publication, 12 June 2015; doi:10.1038/cdd.2015.81