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The Physical Universe
1961
Physics today
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Krauskopf and Arthur Beiser, Twelth Edition, McGraw-Hill (2006)
Final Grade Your final grade will be determined by considering the following components at the indicated weights. ...
doi:10.1063/1.3057394
fatcat:3cb37rhulfg35midk43r43eiji
Sleep and Ventricular Premature Beats
1974
Circulation
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GILLIS, PH.D. ARTHUR RAINES, PH.D. DELBERT E. ENANS, PH.D. BAP{RIE LEVITT, M.D. FRANK G. STANDAERT, M.RA, THIBODEALx H, BARR L: Antiarrhythmic properties of chlordiazepoxide. Circulation, in press 5. ...
doi:10.1161/01.cir.50.4.863-a
pmid:4138393
fatcat:puakr4evgndx3oqlfh7paex6la
Acid-Mediated Tumor Invasion: a Multidisciplinary Study
2006
Cancer Research
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The acid-mediated tumor invasion hypothesis proposes altered glucose metabolism and increased glucose uptake, observed in the vast majority of clinical cancers by fluorodeoxyglucose-positron emission tomography, are critical for development of the invasive phenotype. In this model, increased acid production due to altered glucose metabolism serves as a key intermediate by producing H + flow along concentration gradients into adjacent normal tissue. This chronic exposure of peritumoral normal
doi:10.1158/0008-5472.can-05-4193
pmid:16707446
fatcat:57cyqkks4jgrlaphasquxiyfyi
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... sue to an acidic microenvironment produces toxicity by: (a) normal cell death caused by the collapse of the transmembrane H + gradient inducing necrosis or apoptosis and (b) extracellular matrix degradation through the release of cathepsin B and other proteolytic enzymes. Tumor cells evolve resistance to acidinduced toxicity during carcinogenesis, allowing them to survive and proliferate in low pH microenvironments. This permits them to invade the damaged adjacent normal tissue despite the acid gradients. Here, we describe theoretical and empirical evidence for acid-mediated invasion. In silico simulations using mathematical models provide testable predictions concerning the morphology and cellular and extracellular dynamics at the tumor-host interface. In vivo experiments confirm the presence of peritumoral acid gradients as well as cellular toxicity and extracellular matrix degradation in the normal tissue exposed to the acidic microenvironment. The acid-mediated tumor invasion model provides a simple mechanism linking altered glucose metabolism with the ability of tumor cells to form invasive cancers. (Cancer Res 2006; 66(10): 5216-23) Requests for reprints: Robert A. Gatenby,
Protein–like fully reversible tetramerisation and super-association of an aminocellulose
2014
Scientific Reports
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Unusual protein-like, partially reversible associative behaviour has recently been observed in solutions of the water soluble carbohydrates known as 6-deoxy-6-(v-aminoalkyl)aminocelluloses, which produce controllable self-assembling films for enzyme immobilisation and other biotechnological applications. Now, for the first time, we have found a fully reversible self-association (tetramerisation) within this family of polysaccharides. Remarkably these carbohydrate tetramers are then seen to
doi:10.1038/srep03861
pmid:24457430
pmcid:PMC3900928
fatcat:gvdxy5iscfc67hcy3zsfvip6vy
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... iate further in a regular way into supra-molecular complexes. Fully reversible oligomerisation has been hitherto completely unknown for carbohydrates and instead resembles in some respects the assembly of polypeptides and proteins like haemoglobin and its sickle cell mutation. Our traditional perceptions as to what might be considered "protein-like" and what might be considered as "carbohydrate-like" behaviour may need to be rendered more flexible, at least as far as interaction phenomena are concerned. Results As we found with other 6-deoxy-6-(v-aminoalkyl)aminocelluloses 1 , the technique of sedimentation velocity in the analytical ultracentrifuge revealed several components present: the components sedimenting above 1 Svedberg (S 5 10 213 sec, the same unit which is traditionally used, for example, to classify ribosome sizes) follow a step-wise series rule for globular macromolecules: s i varies as i 2/3 , where i is the peak number. There appears consistently in these substances an additional peak however below 1 S at <0.5 S, which does not conform to this rule, and we wanted to find out its relation with the next peak in the series. To do this, a separate type of OPEN SUBJECT AREAS: BIOANALYTICAL CHEMISTRY POLYSACCHARIDES
Comparison of Methyllidocaine and Lidocaine on Arrhythmias Produced by Coronary Occlusion in the Dog
1973
Circulation
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Methyllidocaine, a quarternary ammonium derivative of lidocaine, was tested as a treatment for the ventricular ectopic beats occurring in unanesthetized dogs 24 hours after two-stage ligation of the anterior descending branch of the left coronary artery. The electrocardiogram (lead II) and electroencephalogram were recorded. Methyllidocaine (4 and 8 mg/kg) injected i.v. during a 1-min period produced a significant reduction in ectopic beats with no significant increase in EEG activity.
doi:10.1161/01.cir.47.4.697
pmid:4696791
fatcat:ub5fw2cgyzbfhendjianmorks4
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... (4 and 8 mg/kg) administered similarly caused similar antiarrhythmic effects but produced a significant increase in EEG activity. A dose of 8 mg/kg caused tonic-clonic seizures in three of five dogs. Both drugs were also given i.v. (15 mg/kg) to unanesthetized cats. Methyllidocaine did not induce convulsions in four of four animals whereas lidocaine induced convulsions in three of three animals. It is concluded that methyllidocaine is as effective an antiarrhythmic agent as lidocaine but does not possess the central nervous system excitatory actions observed with lidocaine.
Whole genome sequencing analysis of the cardiometabolic proteome
2019
biorxiv/medrxiv
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The human proteome is a crucial intermediate between complex diseases and their genetic and environmental components, and an important source of drug development targets and biomarkers. Here, we conduct high-depth (22.5x) whole-genome sequencing (WGS) in 1,328 individuals to fully assess the genetic architecture of 257 circulating protein biomarkers of cardiometabolic relevance. We discover 132 independent sequence variant associations ( <7.45×10 ) across the allele frequency spectrum,
doi:10.1101/854752
fatcat:h6qq65njuzghzicxoehfj23ti4
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... 44 new -acting and 11 new acting loci, all of which replicate in an independent cohort (n=1,605, 18.4x WGS). We identify replicating evidence for rare-variant -acting protein quantitative trait loci for five genes, involving both coding and non-coding variation. We find causal links between protein biomarkers and cardiovascular, inflammatory and immune-related diseases. We construct and validate polygenic risk scores that explain up to 45% of protein level variation, and find significant correlation between genetically-predicted biomarker levels and cardiovascular disease risk in UK Biobank.
Population-wide copy number variation calling using variant call format files from 6,898 individuals
[article]
2018
bioRxiv
pre-print
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MotivationCopy number variants (CNVs) are large deletions or duplications at least 50 to 200 base pairs long. They play an important role in multiple disorders, but accurate calling of CNVs remains challenging. Most current approaches to CNV detection use raw read alignments, which are computationally intensive to process.ResultsWe use a regression tree-based approach to call CNVs from whole-genome sequencing (WGS, > 18x) variant call-sets in 6,898 samples across four European cohorts, and
doi:10.1101/504209
fatcat:jwdrikaukzdb7fr4qtjj52olfe
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... ibe a rich large variation landscape comprising 1,320 CNVs. 61.8% of detected events have been previously reported in the Database of Genomic Variants. 23% of high-quality deletions affect entire genes, and we recapitulate known events such as the GSTM1 and RHD gene deletions. We test for association between the detected deletions and 275 protein levels in 1,457 individuals to assess the potential clinical impact of the detected CNVs. We describe the LD structure and copy number variation underlying the association between levels of the CCL3 protein and a complex structural variant (MAF = 0.15, p = 3.6×10-12) affecting CCL3L3, a paralog of the CCL3 gene. We also identify a cis- association between a low-frequency NOMO1 deletion and the protein product of this gene (MAF = 0.02, p = 2.2×10-7), for which no cis- or trans- single nucleotide variant-driven protein quantitative trait locus (pQTL) has been documented to date. This work demonstrates that existing population-wide WGS call-sets can be mined for CNVs with minimal computational overhead, delivering insight into a less well-studied, yet potentially impactful class of genetic variant.AvailabilityThe regression tree based approach, UN-CNVc, is available as an R and bash executable on GitHub at https://github.com/agilly/un-cnvc.Contacteleftheria.zeggini@helmholtz-muenchen.de; arthur.gilly@helmholtz-muenchen.deSupplementary InformationSupplementary information is appended.
Transposon accumulation lines uncover histone H2A.Z-driven integration bias towards environmentally responsive genes
[article]
2018
bioRxiv
pre-print
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Inherited transposition events are important drivers of genome evolution but because transposable element (TE) mobilization is usually rare, its impact on the creation of genetic variation remains poorly characterized. Here, we used a population of A. thaliana epigenetic recombinant inbred lines (epiRILs) to characterize >8000 de novo insertions produced by several TEs families also active in nature. Integration was strongly biased towards genes, with evident deleterious effects. Biases were TE
doi:10.1101/447870
fatcat:armus7e4tbejboyg2rib3wmg3y
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... family-specific and associated with distinct chromatin features. Notably, we demonstrate that the histone variant H2A.Z guides the preferential integration of Ty1/Copia LTR-retrotransposons within environmentally responsive genes and that this guiding function is evolutionary conserved. Finally, we uncover an important role for epigenetic silencing in exacerbating or alleviating the effects of TE insertions on target genes. These findings establish chromatin as a major determinant of the spectrum and functional impact of TE-generated mutations, with important implications for adaptation and evolution.
MultiSig: a new high-precision approach to the analysis of complex biomolecular systems
2013
European Biophysics Journal
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MultiSig is a newly developed mode of analysis of sedimentation equilibrium (SE) experiments in the analytical ultracentrifuge, having the capability of taking advantage of the remarkable precision (*0.1 % of signal) of the principal optical (fringe) system employed, thus supplanting existing methods of analysis through reducing the 'noise' level of certain important parameter estimates by up to orders of magnitude. Long-known limitations of the SE method, arising from lack of knowledge of the
doi:10.1007/s00249-013-0924-y
pmid:23989852
pmcid:PMC3824846
fatcat:vlbmu4kud5g5rf2wv73e4uknci
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... rue fringe number in fringe optics and from the use of unstable numerical algorithms such as numerical differentiation, have been transcended. An approach to data analysis, akin to 'spatial filtering', has been developed, and shown by both simulation and practical application to be a powerful aid to the precision with which near-monodisperse systems can be analysed, potentially yielding information on protein-solvent interaction. For oligo-and poly-disperse systems the information returned includes precise average mass distributions over both cell radial and concentration ranges and mass-frequency histograms at fixed radial positions. The application of MultiSig analysis to various complex heterogenous systems and potentially multiplyinteracting carbohydrate oligomers is described.
Coiled coil type neoglycoproteins presenting three lactose residues
2016
Tetrahedron Letters
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Scaffold design, synthesis and application is relevant for biomedical research. For example, multivalent interactions, such as those between cell surface glycoproteins and lectins can influence the potency and duration of signalling. The spacing between carbohydrates on their native protein scaffold could be important. Herein, the coiled coil design principle is used to generate synthetic coiled coil type glycoproteins, where three lactose residues are grafted to the coil via N-linkages to
doi:10.1016/j.tetlet.2016.02.005
fatcat:5hdlgbhr5fgmhifblbja6aopdu
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... agine. Molecular modelling indicates that the distance between the galactose anomeric carbon atoms on the neoglycoproteins is ~30 Å. The inclusion of lactose was accommodated in both the final heptad towards the N-terminus, or more centrally in the penultimate heptad. In either case, neither the helicity nor the assembly to the trimeric form was unduly altered by the presence of the disaccharide.
Books
1961
College English
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Glargine and degludec: Solution behaviour of higher dose synthetic insulins
2017
Scientific Reports
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2017) Glargine and degludec: solution behaviour of higher dose synthetic insulins. Scientific Reports, 7 (1). 7287/1-7287/11. A note on versions: The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription. For more information, please contact
doi:10.1038/s41598-017-06642-w
pmid:28779138
pmcid:PMC5544765
fatcat:rpgopx4ckbdunhef6554fquvwm
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... @nottingham.ac.uk SCIeNTIFIC RepoRtS | 7: 7287 | Single, double and triple doses of the synthetic insulins glargine and degludec currently used in patient therapy are characterised using macromolecular hydrodynamic techniques (dynamic light scattering and analytical ultracentrifugation) in an attempt to provide the basis for improved personalised insulin profiling in patients with diabetes. Using dynamic light scattering and sedimentation velocity in the analytical ultracentrifuge glargine was shown to be primarily dimeric under solvent conditions used in current formulations whereas degludec behaved as a dihexamer with evidence of further association of the hexamers ("multi-hexamerisation"). Further analysis by sedimentation equilibrium showed that degludec exhibited reversible interaction between mono-and-di-hexamer forms. Unlike glargine, degludec showed strong thermodynamic non-ideality, but this was suppressed by the addition of salt. With such large injectable doses of synthetic insulins remaining in the physiological system for extended periods of time, in some case 24-40 hours, double and triple dose insulins may impact adversely on personalised insulin profiling in patients with diabetes. The ideal insulin profile for any individual with diabetes will fluctuate due to lifestyle variations and metabolic influences -for example hypoglycaemia -so the physiological importance of insulin is vital for glycaemic homeostasis 1 . The biologically active, circulating form of insulin is monomeric in structure and consists of two chains, an A chain of 21 amino acids and a B chain of 30 amino acids (human), linked by two disulfide bridges, A7-B7 and A20-B19. The A chain contains an intra-chain disulfide bridge between A7 and A11. In the presence of zinc ions and at micromolar concentrations, insulin has been shown to dimerise and further associate into hexamers. Hodgkin and colleagues' pioneering work of the' 2-Zn hexamer 2 showed the A chain has an N-terminal helix (A1-A8) linked to an anti-parallel C-terminal helix (A12-A20) 3 . The B chain has a central helix (B8-B19), which is extended by N-and C terminal strands. This is referred to as the crystallographic T conformation, where all six monomers are in the T (T6) conformation. An alternative conformation where the B-chain helix extends all the way to the N-terminal (B1-B19) is referred to as the R conformation. The 4-Zn hexamer discovered by Schlichtkrull 4 and generated by high chloride concentrations showed three of the monomers were in the R form and three in the T form (R3T3), a structure eventually solved by Hodgkin's group. All six monomers are in the R form (R6) in phenol-containing crystals 5 . The R6 hexamer (solution structure) was resolved by NMR and the allosteric equilibrium structure (T-R transition) was also resolved, where it plays an important role in the pharmaceutical formulations of insulin, whereby phenol and chloride are used as antimicrobial and isotonic agents, respectively. It has now been established that the basic insulin structure of three helices with three conserved disulfide bridges is present in all members of the insulin peptide family. Around its hydrophobic core, the insulin monomer has two extensive non-polar surfaces, one of which is flat and mainly aromatic, and concealed on dimer formation
An enzymatically controlled mucoadhesive system for enhancing flavour during food oral processing
2019
npj Science of Food
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While a good mucoadhesive biopolymer must adhere to a mucus membrane, it must also have a good unloading ability. Here, we demonstrate that the biopolymer pullulan is partially digested by human salivary α-amylase, thus acting as a controlled release system, in which the enzyme triggers an increased release of flavour. Our oral processing simulations have confirmed an increase in the bioavailability of aroma and salt compounds as a function of oral pullulan degradation, although the release
doi:10.1038/s41538-019-0043-y
pmid:31304283
pmcid:PMC6602951
fatcat:phd2yue3ojdpvlsqamgphb2bzi
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... tics suggest a rather slow process. One of the greatest challenges in flavour science is to retain and rapidly unload the bioactive aroma and taste compounds in the oral cavity before they are ingested. By developing a cationic pullulan analogue we have, in theory, addressed the "loss through ingestion" issue by facilitating the adhesion of the modified polymer to the oral mucus, to retain more of the flavour in the oral cavity. Dimethylaminoethyl pullulan (DMAE-pullulan) was synthesised for the first time, and shown to bind submaxillary mucin, while still retaining its susceptibility to α-amylase hydrolysis. Although DMAE-pullulan is not currently food grade, we suggest that the synthesis of a sustainable food grade alternative would be a next generation mucoadhesive targeted for the oral cavity.
Application of novel analytical ultracentrifuge analysis to solutions of fungal mannans
2016
European Biophysics Journal
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M) (Gillis et al. 2013 ). These are presented in Fig. 3 . FM-2 and FM-4 both show two peaks, which is consistent with lsg*(s) distributions. ...
MULTISIG was then used to fit the relative concentration proportions of 17 molar masses, logarithmically spaced to achieve a tenfold range, to yield a molar mass distribution (Gillis et al. 2013 ). ...
doi:10.1007/s00249-016-1159-5
pmid:27444285
pmcid:PMC5346442
fatcat:4ieobajpr5a53jjddatb263j6q
Very low depth whole genome sequencing in complex trait association studies
[article]
2017
bioRxiv
pre-print
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2016) , as well as for 249 MANOLIS samples at 4x , and for 1,457 samples at 22x (Gilly, et al., 2018) . ...
Using the unfiltered 1x variant dataset produced the lowest coefficients (Figure 10 .a), whereas well-behaved set of common SNVs (Arthur, et al., 2017) produced the highest, with an average difference ...
doi:10.1101/169789
fatcat:owq2rrd6h5fkvhqffg64xk3ixu
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