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Search Results: 1 - 10 of 401306 matches for " M. Haworth "
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HPLC-UV, MALDI-TOF-MS and ESI-MS/MS Analysis of the Mechlorethamine DNA Crosslink at a Cytosine-Cytosine Mismatch Pair
Pornchai Rojsitthisak, Nutthapon Jongaroonngamsang, Rebecca M. Romero, Ian S. Haworth
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0020745
Abstract: Background Mechlorethamine [ClCH2CH2N(CH3)CH2CH2Cl], a nitrogen mustard alkylating agent, has been proven to form a DNA interstrand crosslink at a cytosine-cytosine (C-C) mismatch pair using gel electrophoresis. However, the atomic connectivity of this unusual crosslink is unknown. Methodology/Principal Findings HPLC-UV, MALDI-TOF-MS, and ESI-MS/MS were used to determine the atomic connectivity of the DNA C-C crosslink formed by mechlorethamine, MALDI-TOF-MS of the HPLC-purified reaction product of mechlorethamine with the DNA duplex d[CTCACACCGTGGTTC]?d[GAACCACCGTGTGAG] (underlined bases are a C-C mismatch pair) indicated formation of an interstrand crosslink at m/z 9222.088 [M?2H+Na]+. Following enzymatic digestion of the crosslinked duplex by snake venom phosphodiesterase and calf intestinal phosphatase, ESI-MS/MS indicated the presence of dC-mech-dC [mech = CH2CH2N(CH3)CH2CH2] at m/z 269.2 [M]2+ (expected m/z 269.6, exact mass 539.27) and its hydrolytic product dC-mech-OH at m/z 329.6 [M]+ (expected m/z 329.2). Fragmentation of dC-mech-dC gave product ions at m/z 294.3 and 236.9 [M]+, which are both due to loss of the 4-amino group of cytosine (as ammonia), in addition to dC and dC+HN(CH3)CH = CH2, respectively. The presence of m/z 269.2 [M]2+ and loss of ammonia exclude crosslink formation at cytosine N4 or O2 and indicate crosslinking through cytosine N3 with formation of two quaternary ammonium ions. Conclusions Our results provide an important addition to the literature, as the first example of the use of HPLC and MS for analysis of a DNA adduct at the N3 position of cytosine.
From observational to dynamic genetics
Claire M. A. Haworth,Oliver S. P. Davis
Frontiers in Genetics , 2014, DOI: 10.3389/fgene.2014.00006
Abstract: Twin and family studies have shown that most traits are at least moderately heritable. But what are the implications of finding genetic influence for the design of intervention and prevention programs? For complex traits, heritability does not mean immutability, and research has shown that genetic influences can change with age, context, and in response to behavioral and drug interventions. The most significant implications for intervention will come when we move from observational genetics to investigating dynamic genetics, including genetically sensitive interventions. Future interventions should be designed to overcome genetic risk and draw upon genetic strengths by changing the environment.
Testing diagnostics of triggered star formation
Thomas J. Haworth,Tim J. Harries,David M. Acreman
Physics , 2012, DOI: 10.1111/j.1365-2966.2012.21838.x
Abstract: We produce synthetic images and SEDs from radiation hydrodynamical simulations of radiatively driven implosion. The synthetically imaged bright rimmed clouds (BRCs) are morphologically similar to those observed in star forming regions. Using nebular diagnostic line-ratios, simulated Very Large Array (VLA) radio images, H{\alpha} imaging and SED fitting we compute the neutral cloud and ionized boundary layer gas densities and temperatures and perform a virial stability analysis for each model cloud. We determine that the neutral cloud temperatures derived by SED fitting are hotter than the dominant neutral cloud temperature by 1 - 2 K due to emission from warm dust. This translates into a change in the calculated cloud mass by 8-35 %. Using a constant mass conversion factor (C{\nu}) for BRCs of different class is found to give rise to errors in the cloud mass of up to a factor of 3.6. The ionized boundary layer (IBL) electron temperature calculated using diagnostic line ratios is more accurate than assuming the canonical value adopted for radio diagnostics of 10^4 K. Both radio diagnostics and diagnostic line ratios are found to underestimate the electron density in the IBL. Each system is qualitatively correctly found to be in a state in which the pressure in the ionized boundary layer is greater than the supporting cloud pressure, implying that the objects are being compressed. We find that observationally derived mass loss estimates agree with those on the simulation grid and introduce the concept of using the mass loss flux to give an indication of the relative strength of photo-evaporative flow between clouds. The effect of beam size on these diagnostics in radio observations is found to be a mixing of the bright rim and ambient cloud and HII region fluxes, which leads to an underestimate of the cloud properties relative to a control diagnostic.
Testing models of triggered star formation: theory and observation
Thomas J. Haworth,Tim J. Harries,David M. Acreman
Physics , 2012,
Abstract: One of the main reasons that triggered star formation is contentious is the failure to accurately link the observations with models in a detailed, quantitative, way. It is therefore critical to continuously test and improve the model details and methods with which comparisons to observations are made. We use a Monte Carlo radiation transport and hydrodynamics code TORUS to show that the diffuse radiation field has a significant impact on the outcome of radiatively driven implosion (RDI) models. We also calculate SEDs and synthetic images from the models to test observational diagnostics that are used to determine bright rimmed cloud conditions and search for signs of RDI.
Genetics of Learning Abilities and Disabilities: Recent Developments from the UK and Possible Directions for Research in China

Robert Plomin,Claire MA Haworth,Oliver SP Davis,
Robert Plomin
,Claire M.A. Haworth,Oliver S.P. Davis

心理学报 , 2008,
Abstract: It is exciting to witness the birth of behavioral genetics in China at a time when the field of genetics is exploding with new discoveries. We begin by discussing the potential for Chinese researchers to sidestep the false starts of previous genetic research on behavior and to become leaders rather than followers in behavioral genetics research. Using learning abilities and disabilities as an example, the rest of the paper considers ways in which quantitative genetic research can go beyond the nature versus...
Anti-tetherin activities in Vpu-expressing primate lentiviruses
Su Yang, Lisa A Lopez, Heiko Hauser, Colin M Exline, Kevin G Haworth, Paula M Cannon
Retrovirology , 2010, DOI: 10.1186/1742-4690-7-13
Abstract: We found that despite the close relatedness of HIV-1 and SIVcpz, the chimpanzee viruses use Nef instead of Vpu to counteract tetherin. Furthermore, SIVcpz Nef proteins had activity against chimpanzee but not human tetherin. This specificity mapped to a short sequence that is present in the cytoplasmic tail of primate but not human tetherins, and this also accounts for the specificity of SIVsm/mac Nef for primate but not human tetherins. In contrast, Vpu proteins from four diverse members of the SIVsyk lineage all displayed an anti-tetherin activity that was active against macaque tetherin. Interestingly, Vpu from a SIVgsn isolate was also found to have activity against human tetherin.Primate lentiviruses show a high degree of flexibility in their use of anti-tetherin factors, indicating a strong selective pressure to counteract tetherin restriction. The identification of an activity against human tetherin in SIVgsn Vpu suggests that the presence of Vpu in the ancestral SIVmus/mon/gsn virus believed to have contributed the 3' half of the HIV-1 genome may have played a role in the evolution of viruses that could counteract human tetherin and infect humans.The release of HIV-1 and other enveloped viruses from the surface of infected cells is reduced by the activity of the interferon-inducible cell surface protein BST-2/CD317/HM1.24/"tetherin" [1-6]. The importance of overcoming this restriction for virus replication is reflected in the growing list of viral proteins that have been shown to possess anti-tetherin activities, with the primate lentiviruses in particular having evolved diverse approaches that include the HIV-1 Vpu, HIV-2 Env and certain SIV Nef and Env proteins [2,3,7-12].Analyses of the interactions between tetherins from different primate species and the anti-tetherin proteins used by viruses that infect those hosts have revealed a high degree of specificity. For example, although all tetherins analyzed to date can block HIV-1 particle release as efficien
Lack of adaptation to human tetherin in HIV-1 Group O and P
Su Jung Yang, Lisa A Lopez, Colin M Exline, Kevin G Haworth, Paula M Cannon
Retrovirology , 2011, DOI: 10.1186/1742-4690-8-78
Abstract: We found a lack of activity against human tetherin for both the Vpu and Nef proteins from group O and P viruses. Furthermore, we found no evidence of anti-human tetherin activity in a fully infectious group O proviral clone, ruling out the possibility of an alternative anti-tetherin factor in this virus. Interestingly, an activity against primate tetherins was retained in the Nef proteins from both a group O and a group P virus. By making chimeras between a functional group M and non-functional group O Vpu protein, we were able to map the first 18 amino acids of group M Vpu as playing an essential role in the ability of the protein to antagonize human tetherin. We further demonstrated the importance of residue alanine-18 for the group M Vpu activity. This residue lies on a diagonal face of conserved alanines in the TM domain of the protein, and is necessary for specific Vpu-tetherin interactions.The absence of human specific anti-tetherin activities in HIV-1 group O and P suggests a failure of these viruses to adapt to human hosts, which may have limited their spread.Tetherin (BST-2/CD317/HM1.24) is an interferon-inducible plasma membrane protein that can inhibit the release of enveloped viruses by physical tethering nascent virions at the cell surface [1,2]. Within the primate lentiviruses, this restriction is counteracted by anti-tetherin activities present in either the Vpu, Nef or Env proteins [1-11]. Several of these interactions are species-specific, suggesting that selection to evolve and maintain anti-tetherin functions has been part of the adaptation of the viruses to their hosts. For example, HIV-1 clade B Vpu counteracts human, but not primate or rodent tetherins [7,12,13], while the SIVmac and SIVcpz Nef proteins antagonize macaque and chimpanzee tetherin, but not the human protein [3-5,7].HIV-1 is classified into four distinct groups that maintain a similar genome organization but are highly divergent in their sequences: M (major), O (outlier), N (non-m
Added Value Measures in Education Show Genetic as Well as Environmental Influence
Claire M. A. Haworth,Kathryn Asbury,Philip S. Dale,Robert Plomin
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0016006
Abstract: Does achievement independent of ability or previous attainment provide a purer measure of the added value of school? In a study of 4000 pairs of 12-year-old twins in the UK, we measured achievement with year-long teacher assessments as well as tests. Raw achievement shows moderate heritability (about 50%) and modest shared environmental influences (25%). Unexpectedly, we show that for indices of the added value of school, genetic influences remain moderate (around 50%), and the shared (school) environment is less important (about 12%). The pervasiveness of genetic influence in how and how much children learn is compatible with an active view of learning in which children create their own educational experiences in part on the basis of their genetic propensities.
Defining a role for fibroblasts in the persistence of chronic inflammatory joint disease
C Buckley, A Filer, O Haworth, G Parsonage, K Raza, M Salmon
Arthritis Research & Therapy , 2005, DOI: 10.1186/ar1512
Abstract: In this lecture I will illustrate how fibroblasts play an important role in regulating the switch from acute resolving to chronic persistent inflammation associated with the pathology of diseases such as rheumatoid arthritis [1]. In chronic inflammation the normal physiological process of the death and emigration of unwanted inflammatory effector cells becomes disordered leading to accumulation of leucocytes [2-4] within lymphoid aggregates that resemble those seen in lymphoid tissue [5]. I will describe how fibroblasts from the rheumatoid joint provide survival and retention signals for leucocytes leading to their inappropriate and persistent accumulation within inflamed tissue [6]. Our work suggests that targeting the stromal microenvironment is likely to be an important strategy for future anti-inflammatory therapies.
No evidence for association between BMI and 10 candidate genes at ages 4, 7 and 10 in a large UK sample of twins
Claire MA Haworth, Lee M Butcher, Sophia J Docherty, Jane Wardle, Robert Plomin
BMC Medical Genetics , 2008, DOI: 10.1186/1471-2350-9-12
Abstract: For 10 single-nucleotide polymorphisms (SNPs) in candidate genes reported to be associated with BMI in adults, we examined associations with BMI in a sample of 5000 children (2500 twin pairs) with BMI data at 4, 7 and 10 years. Association analyses were performed using the Quantitative Transmission Disequilibrium Test and we corrected for multiple testing using the False Discovery Rate.Despite having 80% power to detect associations that account for as little as 0.2% of the variance of BMI, none of the 10 SNPs were significantly associated with BMI at any age, although two SNPs showed trends in the expected direction.The lack of association for these ten previously reported associations, despite our large sample size, is typical of associations between candidate genes and complex traits. However, some of the reported SNP associations with BMI might emerge as we continue to follow the sample into adolescence and adulthood. This report highlights the importance of developmentally appropriate candidate genes.The rise in obesity is not only seen in the adult population – obesity is also becoming more prevalent in childhood and adolescence [see e.g. [1]]. It is possible that obesity that starts in childhood results in additional health and psychological consequences [2,3]. Twin research, across the lifespan, consistently points to substantial genetic influence on individual differences in BMI and obesity [4-6]. Due to the rising levels of overweight and obesity in childhood, and the obvious long-term health problems and costs that early-onset and persistent obesity will cause, there has been an increased interest into the developmental patterns of BMI in childhood and adolescence. Very little is known about the developmental etiology of BMI and obesity in early and middle childhood. Recent research into the prevalence of obesity and overweight in an adolescent sample has demonstrated that weight is a stable phenotype by this stage of development, with little movement bet
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