12,965 research outputs found

    A Simple Hückel Model-Driven Strategy to Overcome Electronic Barriers to Retro-Brook Silylation Relevant to Aryne and Bisaryne Precursor Synthesis

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    ortho-Silylaryl triflate precursors (oSATs) have been responsible for many recent advances in aryne chemistry and are most commonly accessed from the corresponding 2-bromophenol. A retro-Brook O- to C-silyl transfer is a key step in this synthesis but not all aromatic species are amenable to the transformation, with no functionalized bisbenzyne oSATs reported. Simple Hückel models are presented which show that the calculated aromaticity at the brominated position is an accurate predictor of successful retro-Brook reaction, validated synthetically by a new success and a predicted failure. From this, the synthesis of a novel difunctionalized bisaryne precursor has been tested, requiring different approaches to install the two C-silyl groups. The first successful use of a disubstituted o-silylaryl sulfonate bisbenzyne precursor in Diels–Alder reactions is then shown

    Predicting the Remaining Lifespan and Cultivation-Related Loss of Osteogenic Capacity of Bone Marrow Multipotential Stromal Cells Applicable across a Broad Donor Age Range

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    Background and Objectives. Culture expanded multipotential stromal cells (MSCs) have considerable potential for bone regeneration therapy but their wider use is constrained by the lack of simple and predictive assays of functional potency. Extended passaging leads to loss of multipotency but speed of decline depends on MSC donor age. The aim of this study was to develop an assay predictive of MSC culture longevity applicable to a broad donor age range. Materials and Methods. Bone marrow (BM, =7) was obtained from a diverse range (2–72 years) of healthy donors. MSCs were culture expanded to senescence and their osteoprogenitor content, gene expression profiles, epigenetic signature, and telomere behaviour were measured throughout. Output data was combined for modelling purposes. Results. Regardless of donor age, cultures’ osteoprogenitor content correlated better with remaining lifespan (population doublings before senescence, PD-BS) than proliferative history (accrued PDs). Individual gene’s expression or telomere length did not predict PD-BS but methylation of individual CpG islands did, PRAMEF2 in particular ( = 0.775). Coupling the steep relationship of relative SPARC expression with PD-BS ( = −0.753) the formula SPARC × 1/PREMEF2 gave an improved correlation ( = −0.893).Conclusion. A formula based on SPARC mRNA and PRAMEF2 methylation may be used to predict remaining BM-MSC longevity and related loss of multipotentiality independent of donor age

    A space vector PWM technique for a three-level symmetrical six phase drive

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    A space vector pulse-width modulation (SVPWM) algorithm for a three-level symmetrical six-phase drive, based on vector space decomposition (VSD) approach, is for the first time presented and experimentally proven in this paper. The process how to correctly select the optimal switching sequences, based on several starting requirements and conditions for the analysed topology, such that the output phase voltage waveforms do not contain any low order harmonics, is explained in detail. The developed SVPWM algorithm is verified experimentally using a three-level neutral-point-clamped (NPC) converter and a symmetrical six-phase induction machine. Obtained results prove the validity of the developed SVPWM algorithm. The performance of the SVPWM algorithm is compared with the corresponding carrier-based modulation strategy and it is shown that the two techniques yield identical performance. Finally, both simulation and experimental analysis of the voltage and current THD are reported

    Predicting concrete durability from its absorption

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    This paper discusses the current approach for specifying the durability of concrete in structures. The shortcomings of the use of bulk parameters such as strength, water/binder ratio and binder content to specify durability are discussed. Studies carried out over the last 10 years at Dundee University, using simple permeation tests, which are sensitive to curing, cement type and grade of concrete, have shown close association between permeation properties and the durability of concrete. This paper deals with the measurement of concrete durability by the Dundeemodified Initial Surface Absorption Test (ISAT). A wide range of concrete mixes made with ordinary portland cement and blends with pulverized-fuel ash (PFA) and ground-granulated blastfurnace slag were designed. The duration of moist curing was varied from 0 to 28 days, and the maximum aggregate size from 5 to 40mm. All mixes were tested for absorptivity and aspects of durability including freeze/thaw resistance, carbonation, chloride ingress and mechanical wear. The results show that the absorptivity of concrete, measured with the ISAT, could be used as an accurate specification for concrete durability, irrespective of curing, grade or mix constituents. A tentative surface absorptivity classification for durability has been proposed

    Word-level Symbolic Trajectory Evaluation

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    Symbolic trajectory evaluation (STE) is a model checking technique that has been successfully used to verify industrial designs. Existing implementations of STE, however, reason at the level of bits, allowing signals to take values in {0, 1, X}. This limits the amount of abstraction that can be achieved, and presents inherent limitations to scaling. The main contribution of this paper is to show how much more abstract lattices can be derived automatically from RTL descriptions, and how a model checker for the general theory of STE instantiated with such abstract lattices can be implemented in practice. This gives us the first practical word-level STE engine, called STEWord. Experiments on a set of designs similar to those used in industry show that STEWord scales better than word-level BMC and also bit-level STE.Comment: 19 pages, 3 figures, 2 tables, full version of paper in International Conference on Computer-Aided Verification (CAV) 201

    Investigation of phase separation within the generalized Lin-Taylor model for a binary liquid mixture of large hexagonal and small triangular particles

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    The generalized Lin-Taylor model defined on the hexagonal lattice is used to investigate the phase separation in an asymmetric binary liquid mixture consisting of large A (hexagons) and small B (triangles) particles. By considering interaction energies between A-A and A-B pairs of particles that occupy nearest-neighbour cells of the hexagonal lattice, we have derived an exact solution for the considered model system having established a mapping correspondence with the two-dimensional Ising model on its dual triangular lattice. Altogether, six different types of coexistence curves including those with reentrant miscibility regions (i.e. closed-loop coexistence curves) were found in dependence on the relative strength between both coupling constants.Comment: 8 pages, 4 figures, presented at 7th Liblice conference on the Statistical Mechanics of Liquids to be held in Lednice on June 11-16, 200

    A facile method for the stain-free visualization of hierarchical structures with electron microscopy

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    Diblock copolymers form hierarchical morphologies with numerous applications in drug delivery and as nanoreactors. Yet, the visualization of these structures by electron microscopy can be extremely difficult, requiring complex staining techniques with associated health risks and the potential to alter structural morphology. Reported here is the synthesis of diblock copolymers by RAFT containing 3,5-bis(trifluoromethyl)phenyl functionality allowing for facile visualization of their resulting hierarchical structures by TEM with no further sample preparation.P.E.W. thanks the AWE and E.A. thanks Schlumberger for financial support, and J.d.B is grateful for a Marie Curie Intraeuropean Fellowship (project # 273807). This work was also supported by an ERC Starting Investigator Grant (ASPiRe) and a Next Generation Fellowship provided by the Walters-Kundert Foundation.This is the accepted manuscript. The final published version is available from Wiley at http://onlinelibrary.wiley.com/doi/10.1002/pola.27517/abstract

    Identification of hydroxyapatite spherules provides new insight into subretinal pigment epithelial deposit formation in the aging eye.

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    Accumulation of protein- and lipid-containing deposits external to the retinal pigment epithelium (RPE) is common in the aging eye, and has long been viewed as the hallmark of age-related macular degeneration (AMD). The cause for the accumulation and retention of molecules in the sub-RPE space, however, remains an enigma. Here, we present fluorescence microscopy and X-ray diffraction evidence for the formation of small (0.5-20 μm in diameter), hollow, hydroxyapatite (HAP) spherules in Bruch's membrane in human eyes. These spherules are distinct in form, placement, and staining from the well-known calcification of the elastin layer of the aging Bruch's membrane. Secondary ion mass spectrometry (SIMS) imaging confirmed the presence of calcium phosphate in the spherules and identified cholesterol enrichment in their core. Using HAP-selective fluorescent dyes, we show that all types of sub-RPE deposits in the macula, as well as in the periphery, contain numerous HAP spherules. Immunohistochemical labeling for proteins characteristic of sub-RPE deposits, such as complement factor H, vitronectin, and amyloid beta, revealed that HAP spherules were coated with these proteins. HAP spherules were also found outside the sub-RPE deposits, ready to bind proteins at the RPE/choroid interface. Based on these results, we propose a novel mechanism for the growth, and possibly even the formation, of sub-RPE deposits, namely, that the deposit growth and formation begin with the deposition of insoluble HAP shells around naturally occurring, cholesterol-containing extracellular lipid droplets at the RPE/choroid interface; proteins and lipids then attach to these shells, initiating or supporting the growth of sub-RPE deposits

    The British Society for Rheumatology Biologics Registers in Ankylosing Spondylitis (BSRBR-AS) study: Protocol for a prospective cohort study of the long-term safety and quality of life outcomes of biologic treatment

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    This is the final version of the article. Available from BioMed Central via the DOI in this record.BACKGROUND: Axial spondyloarthropathy typically has its onset in early adulthood and can impact significantly on quality of life. In the UK, biologic anti-tumour necrosis factor therapy is recommended for patients who are unresponsive to non-steroidal anti-inflammatory drugs. There remain several unresolved issues about the long-term safety and quality of life outcomes of biologic treatment in axial spondyloarthropathy. Long-term "real-world" surveillance data are required to complement data from randomised controlled trials. METHODS/DESIGN: We are conducting a UK-wide prospective cohort study of patients with axial spondyloarthropathy who are naïve to biologic therapy at the time of recruitment. Those about to commence anti-tumour necrosis factor biologic therapy will enter a "biologic" sub-cohort with other patients assigned to a "non-biologic" sub-cohort. The primary objective is to determine whether the use of biologic therapy is associated with an increased risk of serious infection, while secondary objectives are to assess differences in malignancy, serious comorbidity, all-cause mortality but also assess impact on specific clinical domains (physical health, mental health and quality of life) including work outcomes between biologic and non-biologic patient cohorts. Patients will be followed-up for up to 5 years. Data are obtained at baseline and at standard clinical follow-up visits - at 3, 6 and 12 months and then annually for the biologic cohort and annually for the non-biologic cohort. This study will also collect biological samples for genetic analysis. DISCUSSION: Although biologic therapy is widely used for ankylosing spondylitis patients who are unresponsive to non-steroidal anti-inflammatory drugs, the majority of the available safety information comes from rheumatoid arthritis, where increased infection risk has consistently been shown. However, given the typical demographic differences between rheumatoid arthritis and axial spondyloarthropathy patients, it is important to develop an epidemiologically rigorous cohort of patients receiving biologic therapy to effectively evaluate outcomes with regard not only to safety but also to quantify benefits across clinical, psychosocial and work outcomes. CLINICAL TRIAL REGISTRATION: This is an observational cohort study and clinical trial registration was not required or obtained.BSRBR-AS is funded by the BSR, which in turn receives funding from the manufacturers of the biologic therapies included in this study (currently AbbVie, Pfizer and UCB). Pharmaceutical companies providing funds to BSR do not have a role in the oversight of the study, but they do receive advance notice of publications on which they are able to comment. They do not have access to the data collected but can request analyses of the data, for which additional funds are provided. GJM chairs a Pfizer competitive grant committee for which he receives an honorarium. GJM and GTJ have received separate funding from AbbVie and Pfizer to study spondyloarthritis in the Scotland Registry for Ankylosing Spondylitis (SIRAS) study. LK has received an unrestricted educational grant from UCB. AK has received research funding from Abbvie and Pfizer as well as speaker/chairman fees and payments for attending advisory boards from Abbvie, Pfizer and UCB. The remaining authors have no competing interests
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