Conformational studies on substituted ε-caprolactams by X-ray crystallography and NMR spectroscopy

The synthesis and conformational analysis of ε-caprolactams containing a -COOMe group at the C-6 position is described. The influence of different C-2, C-6 and N substituents on ring conformation was studied using X-ray crystallography and NMR spectroscopy. The results provide evidence that all the analysed caprolactams adopt a chair type conformation with a planar lactam. In the 6-substituted caprolactam, the -COOMe residue prefers to reside in an equatorial position, but can be induced to occupy an axial orientation by the introduction of a bulky tert-butyloxycarbonyl (BOC) group on the lactam nitrogen or by C-2/C-3 ring desaturation. The BOC protected caprolactam was found to undergo exchange between two chair forms as detected by solution NMR, one with the C-6 ester equatorial (30%) and the other with it in the axial position (70%); the latter was observed by X-ray crystallography. For the C-2 dithiocarbamate substituted C-6 methyl ester seven-membered rings, a single chair form is observed for cis-isomers with both substituents equatorial. The analogous trans-isomers, however, exist as two chair forms in a 1 : 1 equilibrium ratio of 1,NC4 and 4C1,N conformers, where either substituent can occupy axial or equatorial positions. This journal i

Hur kvalitetssäkring påverkas av agila arbetsmetoder

Uppsatsen hade syftet att presentera kvalitetssäkringsbrister som eventuellt uppstod vid användandet av agila arbetsmetoder i utvecklingsprojekt. För att identifiera vad som ansågs vitalt för kvalitetssäkring inom agila utvecklingsprojekt utfördes en litteraturstudie som således ledde till framtagandet av en rad centrala beståndsdelar. Utifrån de identifierade centrala beståndsdelarna arbetade vi fram ett ramverk. Detta ramverk användes som grund för framtagandet av en modell som kunde appliceras på en empirisk studie. Den empiriska kvalitativa studien utgick ifrån två fall som arbetade utefter agila arbetsmetoder och vårt ramverk med tillhörande modell applicerades på studien. Resultatet visade att en rad beståndsdelar inte uppfylldes och därmed ledde till brister av kvalitetssäkring i den slutgiltiga produkten. Sambanden mellan resultat och litteratur diskuterades för att analysera de kvalitetssäkringsbrister som uppstod. Vidare forskning av liknande karaktär kan använda sig av det ramverk och den modell vår uppsats tog fram

Common Genetic Variants Found in HLA and KIR Immune Genes in Autism Spectrum Disorder

The “common variant—common disease” hypothesis was proposed to explain diseases with strong inheritance. This model suggests that a genetic disease is the result of the combination of several common genetic variants. Common genetic variants are described as a 5% frequency differential between diseased vs. matched control populations. This theory was recently supported by an epidemiology paper stating that about 50% of genetic risk for autism resides in common variants. However, rare variants, rather than common variants, have been found in numerous genome wide genetic studies and many have concluded that the “common variant—common disease” hypothesis is incorrect. One interpretation is that rare variants are major contributors to genetic diseases and autism involves the interaction of many rare variants, especially in the brain. It is obvious there is much yet to be learned about autism genetics. Evidence has been mounting over the years indicating immune involvement in autism, particularly the HLA genes on chromosome 6 and KIR genes on chromosome 19. These two large multigene complexes have important immune functions and have been shown to interact to eliminate unwanted virally infected and malignant cells. HLA proteins have important functions in antigen presentation in adaptive immunity and specific epitopes on HLA class I proteins act as cognate ligands for KIR receptors in innate immunity. Data suggests that HLA alleles and KIR activating genes/haplotypes are common variants in different autism populations. For example, class I allele (HLA-A2 and HLA-G 14 bp-indel) frequencies are significantly increased by more than 5% over control populations (Table 2). The HLA-DR4 Class II and shared epitope frequencies are significantly above the control populations (Table 2). Three activating KIR genes: 3DS1, 2DS1, and 2DS2 have increased frequencies of 15, 22, and 14% in autism populations, respectively. There is a 6% increase in total activating KIR genes in autism over control subjects. And, more importantly there is a 12% increase in activating KIR genes and their cognate HLA alleles over control populations (Torres et al., 2012a). These data suggest the interaction of HLA ligand/KIR receptor pairs encoded on two different chromosomes is more significant as a ligand/receptor complex than separately in autism

Going for GOLD! Greater Manchester Growing Older with Learning Disabilities: An inclusive research project to reduce social isolation amongst older adults with learning disabilities

This research was part of the Greater Manchester Growing Older with Learning Disabilities (GM GOLD) project, which was carried out by a team of 16 older people with learning disabilities. The aim was to reduce social isolation amongst older adults (aged 50+) with learning disabilities and to find out what makes somewhere an age-friendly place to live for older adults with learning disabilities. The team was supported by 'research buddies' from Manchester Metropolitan University and the partner organisations to conduct interviews and focus groups with 59 older people (aged 50-79 years) with learning disabilities from eight Greater Manchester areas (Bolton, Bury, Manchester, Oldham, Rochdale, Salford, Tameside, Wigan). Later life transitions for people with learning disabilities are particularly disruptive, and they are at particular risk of social isolation and loneliness. People with learning disabilities have the same rights to relationships and to participate in the cultural life of the community as the rest of society. If society, neighbourhoods and communities do not become more inclusive of people with learning disabilities, in addition to the legal, moral and ethical implications, this is likely to result in additional demand for public services

Image-based Search and Retrieval for Biface Artefacts using Features Capturing Archaeologically Significant Characteristics

Archaeologists are currently producing huge numbers of digitized photographs to record and preserve artefact finds. These images are used to identify and categorize artefacts and reason about connections between artefacts and perform outreach to the public. However, finding specific types of images within collections remains a major challenge. Often, the metadata associated with images is sparse or is inconsistent. This makes keyword-based exploratory search difficult, leaving researchers to rely on serendipity and slowing down the research process. We present an image-based retrieval system that addresses this problem for biface artefacts. In order to identify artefact characteristics that need to be captured by image features, we conducted a contextual inquiry study with experts in bifaces. We then devised several descriptors for matching images of bifaces with similar artefacts. We evaluated the performance of these descriptors using measures that specifically look at the differences between the sets of images returned by the search system using different descriptors. Through this nuanced approach, we have provided a comprehensive analysis of the strengths and weaknesses of the different descriptors and identified implications for design in the search systems for archaeology

Identification of Mediator Kinase Substrates in Human Cells using Cortistatin A and Quantitative Phosphoproteomics

Cortistatin A (CA) is a highly selective inhibitor of the Mediator kinases CDK8 and CDK19. Using CA, we now report a large-scale identification of Mediator kinase substrates in human cells (HCT116). We identified over 16,000 quantified phosphosites including 78 high-confidence Mediator kinase targets within 64 proteins, including DNA-binding transcription factors and proteins associated with chromatin, DNA repair, and RNA polymerase II. Although RNA-Seq data correlated with Mediator kinase targets, the effects of CA on gene expression were limited and distinct from CDK8 or CDK19 knockdown. Quantitative proteome analyses, tracking around 7,000 proteins across six time points (0 – 24h), revealed that CA selectively affected pathways implicated in inflammation, growth, and metabolic regulation. Contrary to expectations, increased turnover of Mediator kinase targets was not generally observed. Collectively, these data support Mediator kinases as regulators of chromatin and RNA polymerase II activity and suggest their roles extend beyond transcription to metabolism and DNA repair.Chemistry and Chemical Biolog

Synthesis of fluorinated alkoxyamines and alkoxyamine-initiated nitroxide-mediated precipitation polymerizations of styrene in supercritical carbon dioxide

TIPNO (2,2,5-trimethyl-4-phenyl-3-azahexane-3-nitroxide)-alkoxyamine was found to give reasonably controlled/living nitroxide-mediated (NMP) precipitation polymerizations of styrene in supercritical carbon dioxide (scCO(2)). In contrast under the same conditions, the analogous SG1 (N-tert-butyl-N-(1-diethylphosphono-2,2-dimethylpropyl)nitroxide)-alkoxyamine gave higher rates of polymerization and inferior controlled/living character. The circumvention of the requirement for excess free (nitroxide](0) allowed the study of nitroxide partitioning effects in scCO(2) for three newly synthesized fluorinated alkoxyamines. Two alkoxyamines dissociated into scCO(2)-philic fluorinated TIPNO-nitroxide derivatives, while another contains a similar sized fluorinated "foot". Despite the increased steric bulk about the N-O bond for the novel fluorinated alkoxyamines, all polymerizations proceeded at a similar rate and level of control to the TIPNO system in solution (toluene). PREDICI simulations for the styrene/TIPNO system are used to support extensive partitioning effects observed in scCO(2) for the fluorinated alkoxyamines.Irish Research Council (formerly IRCSET) IUPAC Transnational Call in Polymer Chemistry to F.Aldabbagh. National Science Foundation (NSF CHE-1057927, USA) to R. Braslau.peer-reviewe

Compressed representation of a partially defined integer function over multiple arguments

In OLAP (OnLine Analitical Processing) data are analysed in an n-dimensional cube. The cube may be represented as a partially defined function over n arguments. Considering that often the function is not defined everywhere, we ask: is there a known way of representing the function or the points in which it is defined, in a more compact manner than the trivial one

Microfluidic Chip for Molecular Amplification of Influenza A RNA in Human Respiratory Specimens

A rapid, low cost, accurate point-of-care (POC) device to detect influenza virus is needed for effective treatment and control of both seasonal and pandemic strains. We developed a single-use microfluidic chip that integrates solid phase extraction (SPE) and molecular amplification via a reverse transcription polymerase chain reaction (RT-PCR) to amplify influenza virus type A RNA. We demonstrated the ability of the chip to amplify influenza A RNA in human nasopharyngeal aspirate (NPA) and nasopharyngeal swab (NPS) specimens collected at two clinical sites from 2008–2010. The microfluidic test was dramatically more sensitive than two currently used rapid immunoassays and had high specificity that was essentially equivalent to the rapid assays and direct fluorescent antigen (DFA) testing. We report 96% (CI 89%,99%) sensitivity and 100% (CI 95%,100%) specificity compared to conventional (bench top) RT-PCR based on the testing of n = 146 specimens (positive predictive value = 100%(CI 94%,100%) and negative predictive value = 96%(CI 88%,98%)). These results compare well with DFA performed on samples taken during the same time period (98% (CI 91%,100%) sensitivity and 96%(CI 86%,99%) specificity compared to our gold standard testing). Rapid immunoassay tests on samples taken during the enrollment period were less reliable (49%(CI 38%,61%) sensitivity and 98%(CI 98%,100%) specificity). The microfluidic test extracted and amplified influenza A RNA directly from clinical specimens with viral loads down to 103 copies/ml in 3 h or less. The new test represents a major improvement over viral culture in terms of turn around time, over rapid immunoassay tests in terms of sensitivity, and over bench top RT-PCR and DFA in terms of ease of use and portability