Mutations in cancer cause gain of cysteine, histidine, and tryptophan at the expense of a net loss of arginine on the proteome level

Accumulation of somatic mutations is critical for the transition of a normal cell to become cancerous. Mutations cause amino acid substitutions that change properties of proteins. However, it has not been studied as to what extent the composition and accordingly chemical properties of the cell proteome is altered as a result of the increased mutation load in cancer. Here, we analyzed data on amino acid substitutions caused by mutations in about 2000 protein coding genes from the Cancer Cell Line Encyclopedia that contains information on nucleotide and amino acid alterations in 782 cancer cell lines, and validated the analysis with information on amino acid substitutions for the same set of proteins in the Catalogue of Somatic Mutations in Cancer (COSMIC; v78) in circa 18,000 tumor samples. We found that nonsynonymous single nucleotide substitutions in the analyzed proteome subset ultimately result in a net gain of cysteine, histidine, and tryptophan at the expense of a net loss of arginine. The extraordinary loss of arginine may be attributed to some extent to composition of its codons as well as to the importance of arginine in the functioning of prominent tumor suppressor proteins like p53

Identification of a bacteriocin and its cognate immunity factor expressed by Moraxella catarrhalis

<p>Abstract</p> <p>Background</p> <p>Bacteriocins are antimicrobial proteins and peptides ribosomally synthesized by some bacteria which can effect both intraspecies and interspecies killing.</p> <p>Results</p> <p><it>Moraxella catarrhalis </it>strain E22 containing plasmid pLQ510 was shown to inhibit the growth of <it>M. catarrhalis </it>strain O35E. Two genes (<it>mcbA </it>and <it>mcbB</it>) in pLQ510 encoded proteins predicted to be involved in the secretion of a bacteriocin. Immediately downstream from these two genes, a very short ORF (<it>mcbC</it>) encoded a protein which had some homology to double-glycine bacteriocins produced by other bacteria. A second very short ORF (<it>mcbI</it>) immediately downstream from <it>mcbC </it>encoded a protein which had no significant similarity to other proteins in the databases. Cloning and expression of the <it>mcbI </it>gene in <it>M. catarrhalis </it>O35E indicated that this gene encoded the cognate immunity factor. Reverse transcriptase-PCR was used to show that the <it>mcbA</it>, <it>mcbB</it>, <it>mcbC</it>, and <it>mcbI </it>ORFs were transcriptionally linked. This four-gene cluster was subsequently shown to be present in the chromosome of several <it>M. catarrhalis </it>strains including O12E. Inactivation of the <it>mcbA</it>, <it>mcbB</it>, or <it>mcbC </it>ORFs in <it>M. catarrhalis </it>O12E eliminated the ability of this strain to inhibit the growth of <it>M. catarrhalis </it>O35E. In co-culture experiments involving a <it>M. catarrhalis </it>strain containing the <it>mcbABCI </it>locus and one which lacked this locus, the former strain became the predominant member of the culture after overnight growth in broth.</p> <p>Conclusion</p> <p>This is the first description of a bacteriocin and its cognate immunity factor produced by <it>M. catarrhalis</it>. The killing activity of the McbC protein raises the possibility that it might serve to lyse other <it>M. catarrhalis </it>strains that lack the <it>mcbABCI </it>locus, thereby making their DNA available for lateral gene transfer.</p

Intrinsic Thermodynamics of Protein-Ligand Binding by Isothermal Titration Calorimetry as Aid to Drug Design

Isothermal titration calorimetry (ITC) is one of the main techniques to determine specific interactions between molecules dissolved in aqueous solution. This technique is commonly used in drug development programs when low-molecular-weight molecules are sought that bind tightly and specifically to a protein (disease target) molecule. The method allows a complete thermodynamic characterization of an interaction, i.e., ITC enables direct determination of the model-independent observed interaction change in enthalpy (ΔH) and a model-dependent observed interaction affinity (change in Gibbs free energy, ΔG) in a single experiment. The product of temperature and change in entropy (TΔS) can be obtained by the subtraction of ΔG from ΔH, and the change in heat capacity (ΔC p ) can be determined as a slope of the temperature dependence of the binding ΔH. Despite the apparent value of ITC in characterization of interactions, it is often forgotten that many protein-ligand binding reactions are linked to protonation-deprotonation reactions or various conformational changes. In such cases, it is important to determine the linked-reaction contributions and obtain the intrinsic values of the changes in Gibbs energy (affinity), enthalpy, and entropy. These energy values can then be used in various SAR-type structure-thermodynamics and combined with structure-kinetics correlations in drug design, when searching for small molecules that would bind the protein target molecule. This manuscript provides a detailed protocol on how to determine the intrinsic values of protein-ligand binding thermodynamics by ITC

Below the Belt? Territory and Development in China’s International Rise

China’s internationalization has been heralded by some as a new era of South–South cooperation. Yet such framings of development are pitched at an abstract space of the ‘global South’ which conceals more than it reveals. With some theory moving towards ontologies of ‘global development’, we need to capture both the connectedness and the local specificity of increasingly diffuse processes. This article sets out a more fine-grained understanding of how political territories and processes are imagined and produced by and through China’s internationalization, focusing on infrastructure as a ‘technology’ of territorialization. Much of the focus on China’s internationalization has been on state-to-state relations, but this obscures the ‘omni-channel politics’ that China practises. Using a critical literature review and illustrative case study, this article develops the idea of omni-channel politics to posit a view of ‘twisted’ territories in which political processes and development outcomes are more complex and contingent

Dietary composition modulates brain mass and solubilizable Aβ levels in a mouse model of aggressive Alzheimer's amyloid pathology

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.Abstract Objective Alzheimer's disease (AD) is a progressive neurodegenerative disease of the central nervous system (CNS). Recently, an increased interest in the role diet plays in the pathology of AD has resulted in a focus on the detrimental effects of diets high in cholesterol and fat and the beneficial effects of caloric restriction. The current study examines how dietary composition modulates cerebral amyloidosis and neuronal integrity in the TgCRND8 mouse model of AD. Methods From 4 wks until 18 wks of age, male and female TgCRND8 mice were maintained on one of four diets: (1) reference (regular) commercial chow; (2) high fat/low carbohydrate custom chow (60 kcal% fat/30 kcal% protein/10 kcal% carbohydrate); (3) high protein/low carbohydrate custom chow (60 kcal% protein/30 kcal% fat/10 kcal% carbohydrate); or (4) high carbohydrate/low fat custom chow (60 kcal% carbohydrate/30 kcal% protein/10 kcal% fat). At age 18 wks, mice were sacrificed, and brains studied for (a) wet weight; (b) solubilizable A&#946; content by ELISA; (c) amyloid plaque burden; (d) stereologic analysis of selected hippocampal subregions. Results Animals receiving a high fat diet showed increased brain levels of solubilizable A&#946;, although we detected no effect on plaque burden. Unexpectedly, brains of mice fed a high protein/low carbohydrate diet were 5% lower in weight than brains from all other mice. In an effort to identify regions that might link loss of brain mass to cognitive function, we studied neuronal density and volume in hippocampal subregions. Neuronal density and volume in the hippocampal CA3 region of TgCRND8 mice tended to be lower in TgCRND8 mice receiving the high protein/low carbohydrate diet than in those receiving the regular chow. Neuronal density and volume were preserved in CA1 and in the dentate gyrus. Interpretation Dissociation of A&#946; changes from brain mass changes raises the possibility that diet plays a role not only in modulating amyloidosis but also in modulating neuronal vulnerability. However, in the absence of a study of the effects of a high protein/low carbohydrate diet on nontransgenic mice, one cannot be certain how much, if any, of the loss of brain mass exhibited by high protein/low carbohydrate diet-fed TgCRND8 mice was due to an interaction between cerebral amyloidosis and diet. Given the recent evidence that certain factors favor the maintenance of cognitive function in the face of substantial structural neuropathology, we propose that there might also exist factors that sensitize brain neurons to some forms of neurotoxicity, including, perhaps, amyloid neurotoxicity. Identification of these factors could help reconcile the poor clinicopathological correlation between cognitive status and structural neuropathology, including amyloid pathology.Published versio

Neurochemical Changes in the Mouse Hippocampus Underlying the Antidepressant Effect of Genetic Deletion of P2X7 Receptors.

Recent investigations have revealed that the genetic deletion of P2X7 receptors (P2rx7) results in an antidepressant phenotype in mice. However, the link between the deficiency of P2rx7 and changes in behavior has not yet been explored. In the present study, we studied the effect of genetic deletion of P2rx7 on neurochemical changes in the hippocampus that might underlie the antidepressant phenotype. P2X7 receptor deficient mice (P2rx7-/-) displayed decreased immobility in the tail suspension test (TST) and an attenuated anhedonia response in the sucrose preference test (SPT) following bacterial endotoxin (LPS) challenge. The attenuated anhedonia was reproduced through systemic treatments with P2rx7 antagonists. The activation of P2rx7 resulted in the concentration-dependent release of [3H]glutamate in P2rx7+/+ but not P2rx7-/- mice, and the NR2B subunit mRNA and protein was upregulated in the hippocampus of P2rx7-/- mice. The brain-derived neurotrophic factor (BDNF) expression was higher in saline but not LPS-treated P2rx7-/- mice; the P2rx7 antagonist Brilliant blue G elevated and the P2rx7 agonist benzoylbenzoyl ATP (BzATP) reduced BDNF level. This effect was dependent on the activation of NMDA and non-NMDA receptors but not on Group I metabotropic glutamate receptors (mGluR1,5). An increased 5-bromo-2-deoxyuridine (BrdU) incorporation was also observed in the dentate gyrus derived from P2rx7-/- mice. Basal level of 5-HT was increased, whereas the 5HIAA/5-HT ratio was lower in the hippocampus of P2rx7-/- mice, which accompanied the increased uptake of [3H]5-HT and an elevated number of [3H]citalopram binding sites. The LPS-induced elevation of 5-HT level was absent in P2rx7-/- mice. In conclusion there are several potential mechanisms for the antidepressant phenotype of P2rx7-/- mice, such as the absence of P2rx7-mediated glutamate release, elevated basal BDNF production, enhanced neurogenesis and increased 5-HT bioavailability in the hippocampus

Forward K+ production in subthreshold pA collisions at 1.0 GeV

K+ meson production in pA (A = C, Cu, Au) collisions has been studied using the ANKE spectrometer at an internal target position of the COSY-Juelich accelerator. The complete momentum spectrum of kaons emitted at forward angles, theta < 12 degrees, has been measured for a beam energy of T(p)=1.0 GeV, far below the free NN threshold of 1.58 GeV. The spectrum does not follow a thermal distribution at low kaon momenta and the larger momenta reflect a high degree of collectivity in the target nucleus.Comment: 4 pages, 3 figure

Optimization of radial diffusion coefficients for the proton radiation belt during the CRRES era

Proton flux measurements from the Proton Telescope instrument aboard the CRRES satellite are revisited, and used to drive a radial diffusion model of the inner proton belt at 1.1 ≤ L ≤ 1.65. Our model utilises a physics‐based evaluation of the cosmic ray albedo neutron decay (CRAND) source, and coulomb collisional loss is driven by a drift averaged density model combining results from the International Reference Ionosphere, NRLMSIS‐00 atmosphere and Radio Plasma Imager plasmasphere models, parameterised by solar activity and season. We drive our model using time‐averaged data at L = 1.65 to calculate steady state profiles of equatorial phase space density, and optimise our choice of radial diffusion coefficients based on four defining parameters to minimise the difference between model and data. This is first performed for a quiet period when the belt can be assumed to represent steady state. Additionally, we investigate fitting steady state solutions to time averages taken during active periods where the data exhibits limited deviation from steady state, demonstrated by CRRES measurements following the 24th March 1991 storm. We also discuss a way to make the optimisation process more reliable by excluding periods of variability in plasmaspheric density from any time average. Lastly, we compare our resultant diffusion coefficients to those derived via a similar process in previous work, and diffusion coefficients derived for electrons from ground and in situ observations. We find that higher diffusion coefficients are derived compared with previous work, and suggest more work is required to derive proton diffusion coefficients for different geomagnetic activity levels

China’s Dam Builders: their role in transboundary river management in Southeast Asia

This article investigates China’s role as the world’s largest builder of and investor in large dams, focussing on the Greater Mekong Sub-Region in South-East Asia. It addresses the role Chinese actors play in dam-building as well as the environmental, social, economic and political implications by drawing on case studies from Cambodia and Vietnam. The article finds that China’s dam-building is perceived very differently in different countries of South-East Asia. In Cambodia, the dams in the Greater Mekong Sub-Region are considered instruments of economic growth and development, whereas downstream in Vietnam the dams are seen as potentially undermining national growth, development and security

S. aureus MscL Is a Pentamer In Vivo but of Variable Stoichiometries In Vitro: Implications for Detergent-Solubilized Membrane Proteins

Detergent-induced rearrangements of membrane-protein subunits explain why two MscL channel stoichiometries have been resolved by X-ray crystallography - but S. aureus MscL is truly a pentamer in vivo