Structures of Two Diastereomeric Aldol Products from a New Silicon-Directed Condensation

Hexahydro-3,3,6-trimethyl-5-phenyl- 1 H,7H-pyrrolo[2,1-e][1,3,6,2]dioxazasilonin-7-one, C17H25NO3Si, Mr=319.48. (2S,3R)-anti-Diastereomer (I), orthorhombic, P212121, a= 8-716(4), b=11-677(3), c=17.161(6)A, V=1746(1)A3, Z=4, Dx=1.22 g cm-3, wavelength(Mo Kce) = 0.71073 A, u=1.50 cm-1 F(000)=688, room temperature, final R=0.040 for 1683 reflections with Fo2 greater than 0. (2S,3S)-syn- Diastereomer (II), monoclinic, P21, a=6.633(2), b=14.645(3), c=9.630(2) A, Beta=109.96(2)o, V=879.3(4) A3, Z=2, Dx=1.21 g cm-3, wavelength(Mo Ka)=0.71073 A,u = 1-49 cm-1, F(000)=344, room temperature, final R = 0.042 for 2537 reflections with F2o greater than 0. The compounds have a nine-membered hetero-cyclic ring containing the Si atom, the N atom of the pyrrolidine ring, two O atoms bonded to silicon and a carbonyl C atom. Bond distances in the molecules are normal and equivalent bonds are equal within three times their e.s.d.'s. Isomer (I) shows a disorder in the pyrrolidine ring that is absent in isomer (II).Chemistry and Chemical Biolog

Structure of an anti-Aldol Addition Product of Benzaldehyde and a Pseudoephedrine-Derived O-Silyl Ketene N,O-Acetal

[4S-(4R*,5R*,8R*,9S*)]-2,2,5,6,8-Penta- methyl-4,9-diphenyl- 1,3-dioxa-6-aza-2-silacyclono-nan-7-one, CE2H29NO3Si, Mr = 383.56, monoclinic, P21, a = 6.550 (3), b = 17.318 (6), c = 20.129 (6) A, /3=98.83(3)° , V =2256.2(14) A 3, Z=4, Dx= 1.13 gcm -3, A(Mo Ka) = 0.71073 A,/z = 1.18 cm -1, F(000) = 824, room temperature, R on F = 0.039 for 4305 reflections with Fo 2 > 3cr(Fo2). The two independent molecules in this structure have nearly the same configuration and geometry. The Si atoms are tetrahedrally coordinated, with average Si--C bond distances of 1.842(3)/~ and average Si---O bond distances of 1.636 (7)A; angles at Si differ from 109.5 ° by an average of 3.5 °. The nine-membered rings are fully extended and the planes of the phenyl groups are approximately perpendicular to the nine- membered ring.Chemistry and Chemical Biolog

Design of a Novel Gene Therapy Construct to Achieve Sustained Brain-Derived Neurotrophic Factor Signaling in Neurons.

Brain-derived neurotrophic factor (BDNF) acting through the tropomyosin-related receptor-B (TrkB) is an important signaling system for the maintenance and survival of neurons. Gene therapy using either recombinant adeno-associated virus (AAV) or lentiviral vectors can provide sustained delivery of BDNF to tissues where reduced BDNF signaling is hypothesized to contribute to disease pathophysiology. However, elevation in BDNF at target sites has been shown to lead to a downregulation of TrkB receptors, thereby reducing the effect of chronic BDNF delivery over time. A novel gene sequence has been designed coding both the ligand (BDNF) and the TrkB receptor in a single transgene separated by a short viral-2A sequence. The single transgene is efficiently processed intracellularly in vitro and in vivo to yield the two mature proteins, which are then independently transported to their final cellular locations: TrkB receptors to the cell surface, and BDNF contained within secretory vesicles. To accommodate the coding sequences of both BDNF and TrkB receptors within the narrow confines of the AAV vectors (4.7 kb pairs), the coding region for the pro-domain of BDNF was removed and the signal peptide sequence modified to improve production, intracellular transport, and secretion of mature BDNF (mBDNF). Intracellular processing and efficacy was shown in HEK293 cells and SH-SY5Y neuroblastoma cells using plasmid DNA and after incorporating the TrkB-2A-mBDNF into an AAV2 vector. Increased BDNF/TrkB-mediated intracellular signaling pathways were observed after AAV2 vector transfection while increased TrkB phosphorylation could be detected in combination with neuroprotection from hydrogen peroxide-induced oxidative stress. Correct processing was also shown in vivo in mouse retinal ganglion cells after AAV2 vector administration to the eye. This novel construct is currently being investigated for its efficacy in animal models to determine its potential to progress to human clinical studies in the future

Angiopoietins in Diabetic Retinopathy: Current Understanding and Therapeutic Potential.

Diabetic retinopathy (DR) is the commonest cause of blindness in the working-age population of the developed world. The molecular pathophysiology of DR is complex, and a complete spatiotemporal model of the disease is still being elucidated. Recently, a role for angiopoietin (Ang) proteins in the pathophysiology of DR has been proposed by several research groups, and several aspects of Ang signalling are being explored as novel therapeutic strategies. Here, we review the role of the Ang proteins in two important forms of DR, diabetic macular oedema and proliferative diabetic retinopathy. The function of the Ang proteins in regulating blood vessel permeability and neovascularisation is discussed, and we also evaluate recent preclinical and clinical studies highlighting the potential benefits of modulating Ang signalling as a treatment for DR.MW and PYWM are funded by Medical Research Council (UK) grants. MW, PYWM and AO 386 receive support from The Novo Nordisk UK Research Foundation, the Cambridge Eye Trust and 387 the Jukes Glaucoma Research Fund. AO, PYWM and KRM also hold Fight for Sight (UK) awards. 388 PYWM is also supported by a Clinician Scientist Fellowship Award (G1002570), the Isaac Newton 389 Trust, the UK National Institute of Health Research (NIHR) as part of the Rare Diseases 390 Translational Research Collaboration, and the NIHR Biomedical Research Centre based at 391 Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology. Research in 392 the laboratory is supported by core funding from Wellcome and MRC to the Wellcome-MRC 393 Cambridge Stem Cell Institute.Peer Reviewe

Silicon-directed aldol condensation. Evidence for a pseudorotational mechanism

Mechanistic studies of the reaction of the (S)-prolinol-derived O-silyl ketene N,O-acetal 1 with aromatic aldehydes are reported. Experiments with three 0-silyl ketene N,O-acetals derived from different 1,2-amino alcohols are also described and lead to a coherent mechanistic picture involving pseudorotation of trigonal bipyramidal organosilicon intermediates

Patient and Provider Perspectives on How Trust Influences Maternal Vaccine Acceptance Among Pregnant Women in Kenya

Background Pregnant women and newborns are at high risk for infectious diseases. Altered immunity status during pregnancy and challenges fully vaccinating newborns contribute to this medical reality. Maternal immunization is a strategy to protect pregnant women and their newborns. This study aimed to find out how patient-provider relationships affect maternal vaccine uptake, particularly in the context of a lower middle- income country where limited research in this area exists. Methods We conducted semi-structured, in-depth narrative interviews of both providers and pregnant women from four sites in Kenya: Siaya, Nairobi, Mombasa, and Marsabit. Interviews were conducted in either English or one of the local regional languages. Results We found that patient trust in health care providers (HCPs) is integral to vaccine acceptance among pregnant women in Kenya. The HCP-patient relationship is a fiduciary one, whereby the patients’ trusts is primarily rooted in the provider’s social position as a person who is highly educated in matters of health. Furthermore, patient health education and provider attitudes are crucial for reinstating and fostering that trust, especially in cases where trust was impeded by rumors, community myths and misperceptions, and religious and cultural factors. Conclusion Patient trust in providers is a strong facilitator contributing to vaccine acceptance among pregnant women in Kenya. To maintain and increase immunization trust, providers have a critical role in cultivating a positive environment that allows for favorable interactions and patient health education. This includes educating providers on maternal immunizations and enhancing knowledge of effective risk communication tactics in clinical encounters

3D Seismic reflection evidence for lower crustal intrusions beneath the Faroe–Shetland Basin, NE Atlantic Margin

Lower crustal intrusion is considered to be a common process along volcanic or magma-rich passive margins, including the NE Atlantic Margin, where it is thought to have occurred during phases of Paleogene magmatism, both prior to and during continental break-up between NW Europe and Greenland. Evidence of Paleogene magmatism is prevalent throughout the sub-basins of the Faroe–Shetland Basin as extensive lava flows and pervasive suites of igneous intrusions. However, in contrast with other areas located along the NE Atlantic Margin, no lower crustal reflectivity indicative of lower crustal intrusion has been documented beneath the Faroe–Shetland Basin. The nearest documentation of lower crustal reflectivity and interpretation of lower crustal intrusion to the Faroe–Shetland Basin is NW of the Fugloy Ridge, beneath the Norwegian Basin of the Faroese sector. Despite this, the addition of magma within the lower crust and/or at the Mohorovičić discontinuity is thought to have played a part in Paleogene uplift and the subsequent deposition of Paleocene–Eocene sequences. Advances in sub-basalt seismic acquisition and processing have made significant improvements in facilitating the imaging of deep crustal structures along the NE Atlantic Margin. This study used broadband 3D seismic reflection data to map a series of deep (c. 14–20 km depth) high-amplitude reflections that may represent igneous intrusions within the lower crust beneath the central-northern Corona Ridge. We estimate that the cumulative thicknesses of the reflections may be >5 km in places, which is consistent with published values of magmatic underplating within the region based on geochemical and petrological data. We also estimate that the total volume of lower crustal high-amplitude reflections within the 3D dataset may be >2000 km3. 2D gravity modelling of a seismic line located along the central-northern Corona Ridge supports the interpretation of lower crustal intrusions beneath this area. This study provides evidence of a potential mechanism for Paleogene uplift within the region. If uplift occurred as a result of lower crustal intrusions emplaced within the crust during the Paleogene, then we estimate that c. 300 m of uplift may have been generated within the Corona Ridge area

Optimization of a 42.7 Gb/s wavelength tunable RZ transmitter using a linear spectrogram technique

The optimization of a wavelength tunable RZ transmitter, consisting of an electro-absorption modulator and a SG DBR tunable laser, is carried out using a linear spectrogram based characterization and leads to 1500 km transmission at 42.7 Gb/s independent of the operating wavelength. We demonstrate that, to ensure optimum and consistent transmission performance over a portion of the C-band, the RF drive and bias conditions of the EAM must be varied at each wavelength. The sign and magnitude of the pulse chirp (characterized using the linear spectrographic technique) is therefore tailored to suit the dispersion map of the transmission link. Results achieved show that by optimizing the drive and DC bias applied to the EAM, consistent transmission performance can be achieved over a wide wavelength range. Failure to optimize the EAM drive conditions at each wavelength can lead to serious degradation in system performance