Momentum isotropisation in random potentials

When particles are multiply scattered by a random potential, their momentum distribution becomes isotropic on average. We study this quantum dynamics numerically and with a master equation. We show how to measure the elastic scattering time as well as characteristic isotropisation times, which permit to reconstruct the scattering phase function, even in rather strong disorder.Comment: 5 pages, paper contributed to Lyon BEC 2012; v2 minor changes, version published in prin

Why are we failing to implement imaging studies with radiolabelled new molecular entities in early oncology drug development?

In early drug development advanced imaging techniques can help with progressing new molecular entities (NME) to subsequent phases of drug development and thus reduce attrition. However, several organizational, operational, and regulatory hurdles pose a significant barrier, potentially limiting the impact these techniques can have on modern drug development. Positron emission tomography (PET) of radiolabelled NME is arguably the best example of a complex technique with a potential to deliver unique decision-making data in small cohorts of subjects. However, to realise this potential the impediments to timely inclusion of PET into the drug development process must be overcome. In the present paper, we discuss the value of PET imaging with radiolabelled NME during early anticancer drug development, as exemplified with one such NME. We outline the multiple hurdles and propose options on how to streamline the organizational steps for future studies

Synthesis of carbon-11 radiolabelled transition metal complexes using 11C-dithiocarbamates

A novel radiolabelling method exploiting 11C-dithiocarbamate ligands has been used to generate 11C-labelled Au(I), Au(III), Pd(II) and Pt(II) complexes in high radiochemical yields (71–99%). Labelled complexes were prepared in a rapid one-pot procedure via the substitution reaction of 11C-dithiocarbamate ligands with appropriate transition metal chloride precursors

Theoretical Analysis of a Large Momentum Beamsplitter using Bloch Oscillations

In this paper, we present the implementation of Bloch oscillations in an atomic interferometer to increase the separation of the two interfering paths. A numerical model, in very good agreement with the experiment, is developed. The contrast of the interferometer and its sensitivity to phase fluctuations and to intensity fluctuations are also calculated. We demonstrate that the sensitivity to phase fluctuations can be significantly reduced by using a suitable arrangement of Bloch oscillations pulses

Transport regimes of cold gases in a two-dimensional anisotropic disorder

We numerically study the dynamics of cold atoms in a two-dimensional disordered potential. We consider an anisotropic speckle potential and focus on the classical regime, which is relevant to some recent experiments. First, we study the behavior of particles with a fixed energy and identify different transport regimes. For low energy, the particles are classically localized due to the absence of a percolating cluster. For high energy, the particles undergo normal diffusion and we show that the diffusion constants scale algebraically with the particle energy, with an anisotropy factor which significantly differs from that of the disordered potential. For intermediate energy, we find a transient sub-diffusive regime, which is relevant to the time scale of typical experiments. Second, we study the behavior of a cold-atomic gas with an arbitrary energy distribution, using the above results as a groundwork. We show that the density profile of the atomic cloud in the diffusion regime is strongly peaked and, in particular, that it is not Gaussian. Its behavior at large distances allows us to extract the energy-dependent diffusion constants from experimental density distributions. For a thermal cloud released into the disordered potential, we show that our numerical predictions are in agreement with experimental findings. Not only does this work give insights to recent experimental results, but it may also serve interpretation of future experiments searching for deviation from classical diffusion and traces of Anderson localization.Comment: 19 pages, 16 figure

Carglumic acid enhances rapid ammonia detoxification in classical organic acidurias with a favourable risk-benefit profile: A retrospective observational study

BACKGROUND: Isovaleric aciduria (IVA), propionic aciduria (PA) and methylmalonic aciduria (MMA) are inherited organic acidurias (OAs) in which impaired organic acid metabolism induces hyperammonaemia arising partly from secondary deficiency of N-acetylglutamate (NAG) synthase. Rapid reduction in plasma ammonia is required to prevent neurological complications. This retrospective, multicentre, open-label, uncontrolled, phase IIIb study evaluated the efficacy and safety of carglumic acid, a synthetic structural analogue of NAG, for treating hyperammonaemia during OA decompensation. METHODS: Eligible patients had confirmed OA and hyperammonaemia (plasma NH3 > 60 μmol/L) in ≥1 decompensation episode treated with carglumic acid (dose discretionary, mean (SD) first dose 96.3 (73.8) mg/kg). The primary outcome was change in plasma ammonia from baseline to endpoint (last available ammonia measurement at ≤18 hours after the last carglumic acid administration, or on Day 15) for each episode. Secondary outcomes included clinical response and safety. RESULTS: The efficacy population (received ≥1 dose of study drug and had post-baseline measurements) comprised 41 patients (MMA: 21, PA: 16, IVA: 4) with 48 decompensation episodes (MMA: 25, PA: 19, IVA: 4). Mean baseline plasma ammonia concentration was 468.3 (±365.3) μmol/L in neonates (29 episodes) and 171.3 (±75.7) μmol/L in non-neonates (19 episodes). At endpoint the mean plasma NH3 concentration was 60.7 (±36.5) μmol/L in neonates and 55.2 (±21.8) μmol/L in non-neonates. Median time to normalise ammonaemia was 38.4 hours in neonates vs 28.3 hours in non-neonates and was similar between OA subgroups (MMA: 37.5 hours, PA: 36.0 hours, IVA: 40.5 hours). Median time to ammonia normalisation was 1.5 and 1.6 days in patients receiving and not receiving concomitant scavenger therapy, respectively. Although patients receiving carglumic acid with scavengers had a greater reduction in plasma ammonia, the endpoint ammonia levels were similar with or without scavenger therapy. Clinical symptoms improved with therapy. Twenty-five of 57 patients in the safety population (67 episodes) experienced AEs, most of which were not drug-related. Overall, carglumic acid seems to have a good safety profile for treating hyperammonaemia during OA decompensation. CONCLUSION: Carglumic acid when used with or without ammonia scavengers, is an effective treatment for restoration of normal plasma ammonia concentrations in hyperammonaemic episodes in OA patients

Molecular evolution of viral multifunctional proteins: the case of Potyvirus HC-Pro

[EN] Our knowledge on the mode of evolution of the multifunctional viral proteins remains incomplete. To tackle this problem, here, we have investigated the evolutionary dynamics of the potyvirus multifunctional protein HC-Pro, with particular focus on its functional domains. The protein was partitioned into the three previously described functional domains, and each domain was analyzed separately and assembled. We searched for signatures of adaptive evolution and evolutionary dependencies of amino acid sites within and between the three domains using the entire set of available potyvirus sequences in GenBank. Interestingly, we identified strongly significant patterns of co-occurrence of adaptive events along the phylogenetic tree in the three domains. These patterns suggest that Domain I, whose main function is to mediate aphid transmission, has likely been coevolving with the other two domains, which are involved in different functions but all requiring the capacity to bind RNA. By contrast, episodes of positive selection on Domains II and III did not correlate, reflecting a trade-off between their evolvability and their evolutionary dependency likely resulting from their functional overlap. Covariation analyses have identified several groups of amino acids with evidence of concerted variation within each domain, but interdomain significant covariations were only found for Domains II and III, further reflecting their functional overlappingThis work was supported by grants BFU2012-30805 (SFE) and BFU2012-36346 (MAF) from the Spanish Direccio´n General de Investigacio´n Cientı´fica y Te´cnica and by an EMBO Short-Term Fellowship and the Mentoring Program from the Foundation for Polish Science (BHJ).Hasiów-Jaroszewska, B.; Fares Riaño, MA.; Elena Fito, SF. (2014). Molecular evolution of viral multifunctional proteins: the case of Potyvirus HC-Pro. Journal of Molecular Evolution. 78(1):75-86. https://doi.org/10.1007/s00239-013-9601-0S7586781Adams MJ, Antoniw JF, Beaudoin F (2005) Overview and analysis of the polyprotein cleavage sites in the family Potyviridae. Mol Plant Pathol 6:471–487Atreya CD, Atryea P, Thornbury DW, Pirone TP (1992) Site-directed mutations in the potyvirus HC-Pro gene affect helper component activity, virus accumulation and symptoms expression in infected tobacco plants. Virology 191:106–111Blanc S, López-Moya JJ, Wang R, García-Lampasona S, Thornbury DW, Pirone TP (1997) A specific interaction between coat protein and helper component correlates with aphid transmission of a potyvirus. Virology 231:141–147Blanc S, Ammar ED, García-Lampasona S, Dolja VV, Llave C, Baker J, Pirone TP (1998) Mutations in the potyvirus helper component protein: effects on interactions with virions and aphid stylets. J Gen Virol 79:3119–3122Cantó T, López-Moya JJ, Serra-Yodi MT, Díaz-Ruiz JR, López-Abella D (1995) Different helper component mutations associated with lack of aphid transmissibility in two isolates of potato virus. Phytopathology 85:1519–1524Carrington JC, Freed DD, Sanders TC (1989) Autocatalytic processing of the potyvirus helper component proteinase in Escherichia coli and in vitro. J Virol 63:4459–4463Chung BY, Miller WA, Atkins JF, Firth AE (2008) An overlapping essential gene in the Potyviridae. Proc Natl Acad Sci USA 105:5897–5902Cronin S, Verchot J, Haldeman-Cahill R, Schaad MC, Carrington JC (1995) Long distance movement factor: a transport function of the potyvirus helper component-proteinase. Plant Cell 7:549–559Edgar RC (2004) MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucl Acids Res 32:1792–1797Elena SF, Rodrigo G (2012) Towards and integrated molecular model of plant-virus interactions. Curr Opin Virol 2:713–718Fares MA (2004) SWAPSC: sliding-window analysis procedure to detect selective constraints. Bioinformatics 20:2867–2868Fares MA, McNally D (2006) CAPS: coevolution analysis using protein sequences. Bioinformatics 22:2821–2822Fares MA, Travers AA (2006) A novel method for detecting intramolecular coevolution: adding a further dimension to selective constrains analyses. Genetics 173:9–23Fares MA, Elena SF, Ortiz J, Moya A, Barrio E (2002) A sliding window-based method to detect selective constraints in protein-coding genes and its application to RNA viruses. J Mol Evol 55:509–521Gibbs A, Ohshima K (2010) Potyviruses and the digital revolution. Annu Rev Phytopathol 48:205–223Guo D, Mertis A, Saarma M (1999) Self-association and mapping of interaction domains of helper component of Potato virus A potyvirus. J Gen Virol 80:1127–1131Guo B, Lin J, Ye K (2011) Structure of the autocatalytic cysteine protease domain of potyvirus helper-component proteinase. J Biol Chem 286:21937–21943Haikonen T, Rajamäki ML, Tian YP, Valkonen JPT (2013) Mutation of a short variable region in HC-Pro protein of Potato virus A affects interactions with microtubule-associated protein and induces necrotic responses in tobacco. Mol Plant Microbe Interact 26:721–733Hall TA (1999) BIOEDIT: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucl Acids Symp Ser 41:95–98Hughes AL (2009) Small effective population sizes and rare nonsynonymous variants in potyviruses. Virology 393:127–134Jones DT (1999) Protein secondary structure prediction based on position-specific scoring matrices. J Mol Biol 292:195–202Kasschau KD, Carrington JC (1995) Requirement for HC-Pro processing during genome amplification of Tobacco etch potyvirus. Virology 209:268–273Kasschau KD, Carrington JC (2001) Long-distance movement and replication maintenance functions correlate with silencing suppression activity of potyviral HC-Pro. Virology 285:71–81Kasschau KD, Cronin S, Carrington JC (1997) Genome amplification and long-distance movement functions associated with the central domain of Tobacco etch potyvirus helper component-proteinase. Virology 228:251–262Kosakovsky Pond SL, Frost SDW (2005a) DATAMONKEY: rapid detection of selective pressure on individual sites of codon alignments. Bioinformatics 21:2531–2533Kosakovsky Pond SL, Frost SDW (2005b) Not so different after all: a comparison of methods for detecting amino acid sites under selection. Mol Biol Evol 22:1208–1222Kosakovsky Pond SL, Posada D, Gravenor MB, Woelk CH, Frost SDW (2006) Automated phylogenetic detection of recombination using a genetic algorithm. Mol Biol Evol 23:1891–1901Lakatos L, Csorba T, Pantaleo V, Chapman EJ, Carrington JC, Liu YP, Dojla VV, Calvino LF, López-Moya JJ, Burgyan J (2006) Small RNA binding is a common strategy to suppress RNA silencing by several viral suppressors. EMBO J 25:2768–2780Lalić J, Elena SF (2012) Magnitude and sign epistasis among deleterious mutations in a positive-sense plant RNA virus. Heredity 109:71–77Leigh JW, Susko E, Baumgartner M, Roger AJ (2008) Testing congruence in phylogenomic analysis. Syst Biol 57:104–115Li WH (1993) Unbiased estimation of the rates of synonymous and nonsynonymous substitution. J Mol Evol 36:96–99Llave C, Kasschau KD, Carrington JC (2000) Virus-encoded suppressor of posttranscriptional gene silencing targets a maintenance step in the silencing pathway. Proc Natl Acad Sci USA 97:13401–13406Maia S, Haenni AL, Bernardi F (1996) Potyviral HC-Pro: a multifunctional protein. J Gen Virol 77:1335–1341Martin DP, Lemey P, Lott M, Moulton V, Posada D, Lefeuvre P (2010) RDP3: a flexible and fast computer program for analyzing recombination. Bioinformatics 26:2462–2463Moroni E, Morra G, Colombo G (2012) Molecular dynamics simulations of Hsp90 with an eye to inhibitor design. Pharmaceuticals 5:944–962Peng YH, Kadoury D, Gaol-On A, Huet H, Wang Y, Raccah B (1998) Mutations in HC-Pro gene of Zucchini yellow mosaic potyvirus: effects on aphid transmission and binding to purified virions. J Gen Virol 79:897–904Plisson C, Drucker M, Blanc S, German-Retana S, Le Gall O, Thomas D, Bron P (2003) Structural characterization of HC-Pro a plant virus multifunctional protein. J Biol Chem 278:23753–23761Posada D, Crandall KA (1998) MODELTEST: testing the model of DNA substitution. Bioinformatics 14:817–818Revers F, Le Gall O, Candresse T, Maule J (1999) New advances in understanding the molecular biology of plant/potyvirus interaction. Mol Plant Microbe Interact 12:367–376Riechmann JL, Lain S, García JA (1992) Highlights and prospects of potyvirus molecular biology. J Gen Virol 73:1–16Roy A, Kucukural A, Zhang Y (2010) I-TASSER: a unified platform for automated protein structure and function prediction. Nat Protoc 5:725–738Ruiz-Ferrer V, Boskovic J, Alfonso C, Rivas G, Llorca O, López-Abella D, López-Moya JJ (2005) Structural analysis of Tobacco etch potyvirus HC-pro oligomers involved in aphid transmission. J Virol 79:3758–3765Shiboleth YM, Haronsky E, Leibman D, Arazi T, Wassenegger M, Whitham SA, Gaba V, Gal-On A (2007) The conserved FRNK box in HC-Pro, a plant viral suppressor of gene silencing, is required for small RNA binding and mediates symptom development. J Virol 81:13135–13148Smoot M, Ono K, Ruschelnski J, Wang PL, Ideker T (2011) CYTOSCAPE 2.8: new features for data integration and network visualization. Bioinformatics 27:431–432Syller J (2006) The roles and mechanisms of helper component proteins encoded by potyviruses and caulimoviruses. Physiol Mol Plant Pathol 67:119–130Tamura K, Peterson D, Peterson N, Stecher G, Nei M, Kumar S (2011) MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol 28:2731–2739Torres-Barceló C, Martín S, Daròs JA, Elena SF (2008) From hypo- to hypersuppression: effect of amino acid substitutions on the RNA-silencing suppressor activity of Tobacco etch potyvirus HC-Pro. Genetics 180:1039–1049Torres-Barceló C, Daròs JA, Elena SF (2010a) Compensatory molecular evolution of HC-Pro, an RNA-silencing suppressor from a plant RNA virus. Mol Biol Evol 27:543–551Torres-Barceló C, Daròs JA, Elena SF (2010b) HC-Pro hypo- and hypersuppressor mutants: differences in viral siRNA accumulation in vivo and siRNA binding activity in vitro. Arch Virol 155:251–254Urcuqui-Inchima S, Walter J, Drugeon G, German-Retans S, Haeni AL, Candresse T, Bernardi F, Le Gall O (1999) Potyvirus HC-Pro self-interaction in the yeast two hybrid system and delineation of the interaction domain involved. Virology 258:95–99Urcuqui-Inchima S, Maia IG, Arruda P, Haenni AL, Bernardi F (2000) Deletion mapping of the potyviral helper component-proteinase reveals two regions involved in RNA binding. Virology 268:104–111Urcuqui-Inchima S, Haenni AL, Bernardi F (2001) Potyvirus proteins: a wealth of functions. Virus Res 74:157–175Varrelmann M, Maiss E, Pilot R, Palkovics L (2007) Use of pentapeptide-insertion scanning mutagenesis for functional mapping of the Plum pox virus helper component proteinase suppressor of gene silencing. J Gen Virol 88:10051015Ward CW, Shukla DD (1991) Taxonomy of potyviruses: current problems and some solutions. Intervirology 32:269–296Wu S, Zhang Y (2007) LOMETS: a local meta-threading-server for protein structure prediction. Nucl Acids Res 35:3375–3382Yang Z, Bielawski JP (2000) Statistical methods for detecting molecular adaptation. Trends Ecol Evol 15:496–503Yap YK, Duangjit J, Panyim S (2009) N-terminal of Papaya ringspot virus type-W (PRSV-W) helper component proteinase (HC-Pro) is essential for PRSV systemic infection in zucchini. Virus Genes 38:461–467Zheng H, Yan F, Lu Y, Sun L, Lin L, Cai L, Hou M, Chen J (2010) Mapping the self-interaction domains of TuMV HC-pro and the subcellular localization of the protein. Virus Genes 42:110–11