Probing elastic and inelastic breakup contributions to intermediate-energy two-proton removal reactions

The two-proton removal reaction from 28Mg projectiles has been studied at 93 MeV/u at the NSCL. First coincidence measurements of the heavy 26Ne projectile residues, the removed protons and other light charged particles enabled the relative cross sections from each of the three possible elastic and inelastic proton removal mechanisms to be determined. These more final-state-exclusive measurements are key for further interrogation of these reaction mechanisms and use of the reaction channel for quantitative spectroscopy of very neutron-rich nuclei. The relative and absolute yields of the three contributing mechanisms are compared to reaction model expectations - based on the use of eikonal dynamics and sd-shell-model structure amplitudes.Comment: Accepted for publication in Physical Review C (Rapid Communication

Elastic breakup cross sections of well-bound nucleons

The 9Be(28Mg,27Na) one-proton removal reaction with a large proton separation energy of Sp(28Mg)=16.79 MeV is studied at intermediate beam energy. Coincidences of the bound 27Na residues with protons and other light charged particles are measured. These data are analyzed to determine the percentage contributions to the proton removal cross section from the elastic and inelastic nucleon removal mechanisms. These deduced contributions are compared with the eikonal reaction model predictions and with the previously measured data for reactions involving the re- moval of more weakly-bound protons from lighter nuclei. The role of transitions of the proton between different bound single-particle configurations upon the elastic breakup cross section is also quantified in this well-bound case. The measured and calculated elastic breakup fractions are found to be in good agreement.Comment: Phys. Rev. C 2014 (accepted

Cost-effectiveness of oral alitretinoin in patients with severe chronic hand eczema - a long-term analysis from a Swiss perspective

BACKGROUND: The impact on patients suffering from chronic hand eczema (CHE) is enormous, as no licensed systemic treatment option with proven efficacy for CHE is available. Alitretinoin is a novel agent which showed high clinical efficacy in patients with severe, refractory CHE. We assessed the cost-effectiveness of alitretinoin for CHE patient treatment from a Swiss third party payer perspective. A further objective of this study was to determine the burden of disease in Switzerland. METHODS: A long-term Markov cohort simulation model was used to estimate direct medical costs (euro) and clinical effectiveness (quality adjusted life years, QALYs) of treating severe CHE patients with alitretinoin. Comparison was against the standard treatment of supportive care (optimised emollient therapy). Information on response rates were derived from a randomized controlled clinical trial. Costs were considered from the perspective of the Swiss health system. Swiss epidemiological data was derived from official Swiss Statistic institutions. RESULTS: Annual costs of alitretinoin treatment accounted for 2'212 euro. After a time horizon of 22.4 years, average remaining long-term costs accounted for 42'208 euro or 38'795 euro in the alitretinoin and the standard treatment arm, respectively. Compared with the standard therapy, the addition of alitretinoin yielded an average gain of 0.230 QALYs at the end of the simulation. Accordingly, the incremental cost-effectiveness ratio resulted in 14'816 euro/QALY gained. These results were robust to changes in key model assumptions. CONCLUSION: The therapy for CHE patients is currently insufficient. In our long-term model we identified the treatment with alitretinoin as a cost-effective alternative for the therapy of CHE patients in Switzerland

Isospin symmetry at high spin studied via nucleon knockout from isomeric states

One-neutron knockout reactions have been performed on a beam of radioactive 53Co in a high-spin isomeric state. The analysis is shown to yield highly-selective population of high-spin states in an exotic nucleus with a significant cross section, and hence represents a technique that is applicable to the planned new generation of fragmentation-based radioactive beam facilities. Additionally, the relative cross sections among the excited states can be predicted to a high level of accuracy when reliable shell-model input is available. The work has resulted in a new level scheme, up to the 11+ band-termination state, of the proton-rich nucleus 52Co (Z = 27, N = 25). This has in turn enabled a study of mirror energy differences in the A = 52 odd-odd mirror nuclei, interpreted in terms of isospin-non-conserving (INC) forces in nuclei. The analysis demonstrates the importance of using a full set of J-dependent INC terms to explain the experimental observations

Covalent Protein Modification with ISG15 via a Conserved Cysteine in the Hinge Region

The ubiquitin-like protein ISG15 (interferon-stimulated gene of 15 kDa) is strongly induced by type I interferons and displays antiviral activity. As other ubiquitin-like proteins (Ubls), ISG15 is post-translationally conjugated to substrate proteins by an isopeptide bond between the C-terminal glycine of ISG15 and the side chains of lysine residues in the substrates (ISGylation). ISG15 consists of two ubiquitin-like domains that are separated by a hinge region. In many orthologs, this region contains a single highly reactive cysteine residue. Several hundred potential substrates for ISGylation have been identified but only a few of them have been rigorously verified. In order to investigate the modification of several ISG15 substrates, we have purified ISG15 conjugates from cell extracts by metal-chelate affinity purification and immunoprecipitations. We found that the levels of proteins modified by human ISG15 can be decreased by the addition of reducing agents. With the help of thiol blocking reagents, a mutational analysis and miRNA mediated knock-down of ISG15 expression, we revealed that this modification occurs in living cells via a disulphide bridge between the substrates and Cys78 in the hinge region of ISG15. While the ISG15 activating enzyme UBE1L is conjugated by ISG15 in the classical way, we show that the ubiquitin conjugating enzyme Ubc13 can either be classically conjugated by ISG15 or can form a disulphide bridge with ISG15 at the active site cysteine 87. The latter modification would interfere with its function as ubiquitin conjugating enzyme. However, we found no evidence for an ISG15 modification of the dynamin-like GTPases MxA and hGBP1. These findings indicate that the analysis of potential substrates for ISG15 conjugation must be performed with great care to distinguish between the two types of modification since many assays such as immunoprecipitation or metal-chelate affinity purification are performed with little or no reducing agent present

The Herpesvirus Associated Ubiquitin Specific Protease, USP7, Is a Negative Regulator of PML Proteins and PML Nuclear Bodies

The PML tumor suppressor is the founding component of the multiprotein nuclear structures known as PML nuclear bodies (PML-NBs), which control several cellular functions including apoptosis and antiviral effects. The ubiquitin specific protease USP7 (also called HAUSP) is known to associate with PML-NBs and to be a tight binding partner of two herpesvirus proteins that disrupt PML NBs. Here we investigated whether USP7 itself regulates PML-NBs. Silencing of USP7 was found to increase the number of PML-NBs, to increase the levels of PML protein and to inhibit PML polyubiquitylation in nasopharyngeal carcinoma cells. This effect of USP7 was independent of p53 as PML loss was observed in p53-null cells. PML-NBs disruption was induced by USP7 overexpression independently of its catalytic activity and was induced by either of the protein interaction domains of USP7, each of which localized to PML-NBs. USP7 also disrupted NBs formed from some single PML isoforms, most notably isoforms I and IV. CK2α and RNF4, which are known regulators of PML, were dispensable for USP7-associated PML-NB disruption. The results are consistent with a novel model of PML regulation where a deubiquitylase disrupts PML-NBs through recruitment of another cellular protein(s) to PML NBs, independently of its catalytic activity

A Viral Ubiquitin Ligase Has Substrate Preferential SUMO Targeted Ubiquitin Ligase Activity that Counteracts Intrinsic Antiviral Defence

Intrinsic antiviral resistance represents the first line of intracellular defence against virus infection. During herpes simplex virus type-1 (HSV-1) infection this response can lead to the repression of viral gene expression but is counteracted by the viral ubiquitin ligase ICP0. Here we address the mechanisms by which ICP0 overcomes this antiviral response. We report that ICP0 induces the widespread proteasome-dependent degradation of SUMO-conjugated proteins during infection and has properties related to those of cellular SUMO-targeted ubiquitin ligases (STUbLs). Mutation of putative SUMO interaction motifs within ICP0 not only affects its ability to degrade SUMO conjugates, but also its capacity to stimulate HSV-1 lytic infection and reactivation from quiescence. We demonstrate that in the absence of this viral countermeasure the SUMO conjugation pathway plays an important role in mediating intrinsic antiviral resistance and the repression of HSV-1 infection. Using PML as a model substrate, we found that whilst ICP0 preferentially targets SUMO-modified isoforms of PML for degradation, it also induces the degradation of PML isoform I in a SUMO modification-independent manner. PML was degraded by ICP0 more rapidly than the bulk of SUMO-modified proteins in general, implying that the identity of a SUMO-modified protein, as well as the presence of SUMO modification, is involved in ICP0 targeting. We conclude that ICP0 has dual targeting mechanisms involving both SUMO- and substrate-dependent targeting specificities in order to counteract intrinsic antiviral resistance to HSV-1 infection

One-neutron pickup into Ca 49: Bound neutron g9/2 spectroscopic strength at N=29

none14sinoneGade, A.; Tostevin, J.A.; Bader, V.; Baugher, T.; Bazin, D.; Berryman, J.S.; Brown, B.A.; Hartley, D.J.; Lunderberg, E.; Recchia, F.; Stroberg, S.R.; Utsuno, Y.; Weisshaar, D.; Wimmer, K.Gade, A.; Tostevin, J. A.; Bader, V.; Baugher, T.; Bazin, D.; Berryman, J. S.; Brown, B. A.; Hartley, D. J.; Lunderberg, E.; Recchia, Francesco; Stroberg, S. R.; Utsuno, Y.; Weisshaar, D.; Wimmer, K

One-neutron pickup into Ca49: Bound neutron g9/2 spectroscopic strength at N=29

The highly selective, intermediate-energy heavy-ion-induced neutron-pickup reaction, in combination with γ-ray spectroscopy using the γ-ray energy-tracking in-beam nuclear array (GRETINA), is shown to provide reliable relative spectroscopic strengths for high-ℓ orbitals in nuclei more neutron rich than the projectile. The reaction mechanism gives a significant final-state-spin alignment that is validated through γ-ray angular-distribution measurements enabled by the position sensitivity of GRETINA. This is the first time that γ-ray angular distributions could be extracted from a high-luminosity, fast-beam reaction other than inelastic scattering. This holds great promise for the restriction and assignment of Jπ quantum numbers in exotic nuclei. We advance this approach to study the crucial N=28 shell closure and extract the ratio g9/2:f5/2 of bound neutron single-particle strengths in Ca49, a benchmark for emerging multi-shell ab initio and configuration-interaction theories that are applicable along the Ca isotopic chain