New Strategies for the functionalization of N-heterocycles using Li-, Mg- and Zn-organometallics

The first part of this work focused on the development of a convenient and general regioselective functionalization of all ring positions of the 7-azaindole scaffold. To this end, starting from simple 2-amino-5-bromopyridine an appropriately substituted azaindole precursor was prepared which allowed us to functionalize the 7-azaindole ring in a predictable manner using a combination of directed metalation, halogen/magnesium and sulfoxide/magnesium exchange. Furthermore, the general preparation of various heteroarylmethylzinc reagents by LiCl-promoted zinc insertion into the corresponding chloromethyl heteroarenes, along with a facile and straightforward synthesis of these chloromethyl precursors displayed a major part in this work. The obtained zinc compounds were subjected to Pd-catalyzed cross-couplings, Cu-mediated acylations, Cu-catalyzed allylations and addition reactions to aldehydes. In addition, they proved to be versatile intermediates for the construction of fused N- and O-heterocycles and gave access to an analogue of a reported CB1 modifier. Finally, a lithiation/transmetalation strategy for the metalation of sensitive functionalized arenes and heteroarenes was developed, using the strong amide base TMPLi in the presence of metal salts such as ZnCl2, MgCl2, CuCN and LaCl3. This in situ trapping method not only allowed the metalation and functionalization of sensitive heteroarenes, but also provided metalated intermediates with a different regioselectivity to the one produced with moderately powerful bases such as TMPZnCl•LiCl or TMPMgCl•LiCl, giving access to higly functionalized organometallics difficult to prepare otherwise

Investigations into the nature of the pomeron

We investigate the nature of the Pomeranchukon (Pomeron P) singularity in the complex angular momentum plane. To distinguish between simple pole and branch point, we establish and test the factorization rule when Pomeron is exchanged in three particle final states. Further we predict results on the polarization states of resonances when definite parity for Pomeron-pole and mixtures of parities for Pomeron-cut is exchanged. To make comparison of the Pomeron trajectory with other low-lying meson trajectories, we also establish a factorization test for the Rho trajectory and compare it with experimental results. In Chapter I, we give a general review of Regge-pole theory and also show what difficulties we have with the Pomeron trajectory as compared to other ordinary trajectories. This chapter lays the groundwork, explains the problem, and serves as a motivation for the work which was undertaken. In Chapter II, factorization test for the Pomeron is suggested for reactions with three particle in the final states. It is applied to the available experimental data on πN→ ππN and NN→πNN and is found to be satisfied reasonably well. This gives one evidence that Pomeron is a simple pole. In Chapter III, we establish a direct test of factorization for the Rho and show from the experimental data, that there is a significant failure of the factorization and also mixture of parities is exchanged in the Rho dominated reactions. It is suggested that cuts play an Important part at high energy and indication exists that the Rho particle is a parity doublet

New Strategies for the functionalization of N-heterocycles using Li-, Mg- and Zn-organometallics

The first part of this work focused on the development of a convenient and general regioselective functionalization of all ring positions of the 7-azaindole scaffold. To this end, starting from simple 2-amino-5-bromopyridine an appropriately substituted azaindole precursor was prepared which allowed us to functionalize the 7-azaindole ring in a predictable manner using a combination of directed metalation, halogen/magnesium and sulfoxide/magnesium exchange. Furthermore, the general preparation of various heteroarylmethylzinc reagents by LiCl-promoted zinc insertion into the corresponding chloromethyl heteroarenes, along with a facile and straightforward synthesis of these chloromethyl precursors displayed a major part in this work. The obtained zinc compounds were subjected to Pd-catalyzed cross-couplings, Cu-mediated acylations, Cu-catalyzed allylations and addition reactions to aldehydes. In addition, they proved to be versatile intermediates for the construction of fused N- and O-heterocycles and gave access to an analogue of a reported CB1 modifier. Finally, a lithiation/transmetalation strategy for the metalation of sensitive functionalized arenes and heteroarenes was developed, using the strong amide base TMPLi in the presence of metal salts such as ZnCl2, MgCl2, CuCN and LaCl3. This in situ trapping method not only allowed the metalation and functionalization of sensitive heteroarenes, but also provided metalated intermediates with a different regioselectivity to the one produced with moderately powerful bases such as TMPZnCl•LiCl or TMPMgCl•LiCl, giving access to higly functionalized organometallics difficult to prepare otherwise

Polymethylmethacrylate cranioplasty using low-cost customised 3D printed moulds for cranial defects – a single Centre experience: technical note

We report our experience with 3D customised cranioplasties for large cranial defects. They were made by casting bone cement in custom made moulds at the time of surgery. Between October 2015 and January 2018, 29 patients underwent the procedure; 25 underwent elective cranioplasties for large cranial defects and four were bone tumour resection and reconstruction cases. The majority of patients (96.5%) reported a satisfactory aesthetic outcome. No infections related to the surgical procedure were observed in the follow-up period. The method proved to be effective and affordable

Biomechanical stability analysis of transpedicular screws combined with sublaminar hook-rod system using the finite element method

Aim To develop and test a new posterior stabilization system by augmenting the posterior hook-rod system with screws and rods. Methods A biomechanical analysis was performed using the finite element method. The anatomical structures were modeled based on computed tomography data. Instrumentation (hooks, rods, and screws) was modeled based on the data obtained by 3D scanning. The discretized model was verified by converging solutions and validated against data from a previously published experiment. A Th12-L1 spinal segment was modeled and modified by removing the body of the L1 vertebra (corpectomy) and the entire L1 vertebra (spondylectomy). The model was additionally modified by incorporating stabilization systems: i) posterior stabilization (transpedicular screws and rods); ii) combined posterior stabilization with sublaminar hooks; and iii) combined anterior (titanium cage) and posterior (sublaminar hooks) stabilization. The rotation angles in each group, and the strains on each part of the three stabilization constructs, were analyzed separately. Results The combined anterior and posterior stabilization system was the stiffest, except in the case of lateral bending, where combined posterior stabilization was superior. Stress analysis showed that the posterior stabilization system was significantly unloaded when augmented with a hook-rod system. A significant strain concentration was calculated in the cranially placed hooks. Conclusion Stiffness analysis showed comparable stiffness between the tested and proposed stabilization construct. Stress analysis showed luxation tendency of the cranially placed hooks, which would most likely lead to system failure

The Photodetector Array Camera and Spectrometer (PACS) on the Herschel Space Observatory

The Photodetector Array Camera and Spectrometer (PACS) is one of the three science instruments on ESA's far infrared and submillimetre observatory. It employs two Ge:Ga photoconductor arrays (stressed and unstressed) with 16x25 pixels, each, and two filled silicon bolometer arrays with 16x32 and 32x64 pixels, respectively, to perform integral-field spectroscopy and imaging photometry in the 60-210\mu\ m wavelength regime. In photometry mode, it simultaneously images two bands, 60-85\mu\ m or 85-125\mu\m and 125-210\mu\ m, over a field of view of ~1.75'x3.5', with close to Nyquist beam sampling in each band. In spectroscopy mode, it images a field of 47"x47", resolved into 5x5 pixels, with an instantaneous spectral coverage of ~1500km/s and a spectral resolution of ~175km/s. We summarise the design of the instrument, describe observing modes, calibration, and data analysis methods, and present our current assessment of the in-orbit performance of the instrument based on the Performance Verification tests. PACS is fully operational, and the achieved performance is close to or better than the pre-launch predictions

ARGOS: the laser guide star system for the LBT

ARGOS is the Laser Guide Star adaptive optics system for the Large Binocular Telescope. Aiming for a wide field adaptive optics correction, ARGOS will equip both sides of LBT with a multi laser beacon system and corresponding wavefront sensors, driving LBT's adaptive secondary mirrors. Utilizing high power pulsed green lasers the artificial beacons are generated via Rayleigh scattering in earth's atmosphere. ARGOS will project a set of three guide stars above each of LBT's mirrors in a wide constellation. The returning scattered light, sensitive particular to the turbulence close to ground, is detected in a gated wavefront sensor system. Measuring and correcting the ground layers of the optical distortions enables ARGOS to achieve a correction over a very wide field of view. Taking advantage of this wide field correction, the science that can be done with the multi object spectrographs LUCIFER will be boosted by higher spatial resolution and strongly enhanced flux for spectroscopy. Apart from the wide field correction ARGOS delivers in its ground layer mode, we foresee a diffraction limited operation with a hybrid Sodium laser Rayleigh beacon combination.12 page(s

Molecular Methods for Detection of Antimicrobial Resistance

ABSTRACT The increase in bacteria harboring antimicrobial resistance (AMR) is a global problem because there is a paucity of antibiotics available to treat multidrug-resistant bacterial infections in humans and animals. Detection of AMR present in bacteria that may pose a threat to veterinary and public health is routinely performed using standardized phenotypic methods. Molecular methods are often used in addition to phenotypic methods but are set to replace them in many laboratories due to the greater speed and accuracy they provide in detecting the underlying genetic mechanism(s) for AMR. In this article we describe some of the common molecular methods currently used for detection of AMR genes. These include PCR, DNA microarray, whole-genome sequencing and metagenomics, and matrix-assisted laser desorption ionization–time of flight mass spectrometry. The strengths and weaknesses of these methods are discussed, especially in the context of implementing them for routine surveillance activities on a global scale for mitigating the risk posed by AMR worldwide. Based on current popularity and ease of use, PCR and single-isolate whole-genome sequencing seem irreplaceable.</jats:p

Science and Adaptive Optics Requirements of MICADO, the E-ELT adaptive optics imaging camera

MICADO is the adaptive optics imaging camera being studied for the E-ELT. Its design has been optimised for use with MCAO, but will have its own SCAO module for the initial operational phase; and in principle could also be used with GLAO or LTAO. In this contribution, we outline a few of the science drivers for MICADO and show how these have shaped its design. The science drivers have led to a number of requirements on the AO system related to astrometry, photometry, and PSF uniformity. We discuss why these requirements have arisen and what might be done about them.Comment: 6 pages, to appear in the proceedings of the AO4ELT conference, held in Paris, 22-26 June 200

Use of optical mapping to sort uropathogenic Escherichia coli strains into distinct subgroups

Optical maps were generated for 33 uropathogenic Escherichia coli (UPEC) isolates. For individual genomes, the NcoI restriction fragments aligned into a unique chromosome map for each individual isolate, which was then compared with the in silico restriction maps of all of the sequenced E. coli and Shigella strains. All of the UPEC isolates clustered separately from the Shigella strains as well as the laboratory and enterohaemorrhagic E. coli strains. Moreover, the individual strains appeared to cluster into distinct subgroups based on the dendrogram analyses. Phylogenetic grouping of these 33 strains showed that 32/33 were the B2 subgroup and 1/33 was subgroup A. To further characterize the similarities and differences among the 33 isolates, pathogenicity island (PAI), haemolysin and virulence gene comparisons were performed. A strong correlation was observed between individual subgroups and virulence factor genes as well as haemolysis activity. Furthermore, there was considerable conservation of sequenced-strain PAIs in the specific subgroups. Strains with different antibiotic-resistance patterns also appeared to sort into separate subgroups. Thus, the optical maps distinguished the UPEC strains from other E. coli strains and further subdivided the strains into distinct subgroups. This optical mapping procedure holds promise as an alternative way to subgroup all E. coli strains, including those involved in infections outside of the intestinal tract and epidemic strains with distinct patterns of antibiotic resistance