| 1. |
|
|
| 2. |
- Aggarwal, M. M., et al.
(författare)
-
Photon and eta production in p plus Pb and p plus C collisions at root(NN)-N-S=17.4 GeV
- 2013
-
Ingår i: Nuclear Physics, Section A. - : Elsevier BV. - 0375-9474. ; 898, s. 14-23
-
Tidskriftsartikel (refereegranskat)abstract
- Measurements of direct photon production in p + Pb and p + C collisions at root(NN)-N-s = 17.4 GeV are presented. Upper limits on the direct photon yield as a function of p(T) are derived and compared to the results for Pb + Pb collisions at root(NN)-N-s = 17.3 GeV. The production of the eta meson, which is an important input to the direct photon signal extraction, has been determined in the eta -> 2 gamma channel for p + C collisions at root(NN)-N-s = 17.4 GeV. (c) 2012 Elsevier B.V. All rights reserved.
|
|
| 3. |
- Aggarwal, M. M., et al.
(författare)
-
Pion freeze-out time in Pb plus Pb collisions at 158 AGeV/c studied via pi(-)/pi(+) and K-/K+ ratios
- 2006
-
Ingår i: European Physical Journal C. Particles and Fields. - : Springer Science and Business Media LLC. - 1434-6044. ; 48:2, s. 343-352
-
Tidskriftsartikel (refereegranskat)abstract
- The effect of the final state Coulomb interaction on particles produced in Pb + Pb collisions at 158AGeV/c has been investigated in the WA98 experiment through the study of the pi(-)/pi(+) and K-/K+ ratios measured as a function of T-m- (m)0. While the ratio for kaons shows no significant T-m dependence, the pi(-)/pi(+) ratio is enhanced at small T-m - (m)0 values with an enhancement that increases with centrality. A silicon pad detector located near the target is used to estimate the contribution of hyperon decays to the pi(-)/pi(+) ratio. The comparison of results with predictions of the RQMD model in which the Coulomb interaction has been incorporated allows to place constraints on the time of the pion freeze-out.
|
|
| 4. |
- Aggarwal, M. M., et al.
(författare)
-
Suppression of high-p(T) neutral pion production in central Pb+Pb collisions at root s(NN)=17.3 GeV relative to p+C and p+Pb collisions
- 2008
-
Ingår i: Physical Review Letters. - 1079-7114. ; 100:24
-
Tidskriftsartikel (refereegranskat)abstract
- Neutral pion transverse momentum spectra were measured in p+C and p+Pb collisions at root s(NN) = 17.4 GeV at midrapidity (2.3 less than or similar to eta(lab)less than or similar to 3.0) over the range 0.7 less than or similar to p(T)less than or similar to 3.5 GeV/c. The spectra are compared to pi(0) spectra measured in Pb+Pb collisions at root s(NN) = 17.3 GeV in the same experiment. For a wide range of Pb+Pb centralities (N-part less than or similar to 300), the yield of pi(0)'s with p(T)greater than or similar to 2 GeV/c is larger than or consistent with the p+C or p+Pb yields scaled with the number of nucleon-nucleon collisions (N-coll), while for central Pb+Pb collisions with N-part greater than or similar to 350, the pi(0) yield is suppressed.
|
|
| 5. |
- Aggarwal, MM, et al.
(författare)
-
Event-by-event fluctuations in particle multiplicities and transverse energy produced in 158A GeVPb plus Pb collisions
- 2002
-
Ingår i: Physical Review C (Nuclear Physics). - 0556-2813. ; 65:5
-
Tidskriftsartikel (refereegranskat)abstract
- Event-by-event fluctuations in the multiplicities of charged particles and photons, and the total transverse energy in 158A GeV Pb+Pb collisions are studied for a wide range of centralities. For narrow centrality bins the multiplicity and transverse energy distributions are found to be near perfect Gaussians. The effect of detector acceptance on the multiplicity fluctuations has been studied and demonstrated to follow statistical considerations. The centrality dependence of the charged particle multiplicity fluctuations in the measured data has been found to agree reasonably well with those obtained from a participant model. However, for photons the multiplicity fluctuations have been found to be lower compared to those obtained from a participant model. The multiplicity and transverse energy fluctuations have also been compared to those obtained from the VENUS event generator.
|
|
| 6. |
- Aggarwal, MM, et al.
(författare)
-
Transverse mass distributions of neutral pions from Pb-208-induced reactions at 158 center dot A GeV
- 2002
-
Ingår i: European Physical Journal C. Particles and Fields. - : Springer Science and Business Media LLC. - 1434-6044. ; 23:2, s. 225-236
-
Tidskriftsartikel (refereegranskat)abstract
- Results on transverse mass spectra of neutral pious measured at central rapidity are presented for impact parameter selected 158-A GeV Pb + Pb-1 and Pb + Nb collisions. The distributions cover the range 0.5 GeV/c(2) less than or equal to MT - Mo less than or equal to 4 GeV/c(2). The change of the spectral shape and the multiplicity with centrality is studied in detail. In going from p+p to semi-peripheral Pb+Pb collisions there is a nuclear enhancement increasing with transverse mass similar to the well known Cronin effect, while for very central collisions this enhancement appears to be weaker than expected.
|
|
| 7. |
- Foerster, Sunniva, et al.
(författare)
-
The first wide-scale drug repurposing screen using the Prestwick Chemical Library (1200 bioactive molecules) against Neisseria gonorrhoeae identifies high in vitro activity of auranofin and many additional drugs
- 2020
-
Ingår i: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS). - : Wiley-Blackwell Publishing Inc.. - 0903-4641 .- 1600-0463. ; 128:3, s. 242-250
-
Tidskriftsartikel (refereegranskat)abstract
- Treatment options for gonorrhoea are scarce. Drug repurposing of bioactive molecules approved for other conditions might therefore be of value. We developed a method for wide-scale, systematic drug repurposing screen to identify molecules with activity against Neisseria gonorrhoeae and screened the Prestwick Chemical Library (1200 FDA-approved drugs). As a proof-of-concept, we further examined one promising and interesting screening hit (auranofin; antirheumatic agent). Three WHO gonococcal reference strains (WHO F, O, P) were used for the Library screening. The strains were grown in presence of a fixed concentration of the library drugs in 384-well plates for 12 hours and the remaining bacterial respiration, to reflect growth, was then quantitatively measured using optical density (OD) 450 nm and a resazurin assay. The activity of auranofin was further examined using in vitro susceptibility testing (minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC)) against genetically diverse antimicrobial-resistant N. gonorrhoeae strains and time-kill assays. Sixty-eight molecules significantly inhibited bacterial growth of WHO F, O and, P. Auranofin showed potent in vitro bactericidal activity (in MIC-, MBC-, and time-kill assays) against four WHO reference strains. No cross resistance between auranofin and any antimicrobial currently or previously used for gonorrhoea treatment was found when examining 51 selected antimicrobial-resistant gonococcal strains. In conclusion, this is the first wide-scale systematic screening effort for repurposing drugs for future treatment of gonorrhoea. Additional studies examining mechanism(s) of action, resistance development, in vivo anti-gonococcal activity, and pharmacokinetics/pharmacodynamics for gonococcal infections of auranofin and several other significant screening hits would be valuable.
|
|
| 8. |
- Gustafsson, Tomas N., et al.
(författare)
-
Bacillus anthracis Thioredoxin Systems, Characterization and Role as Electron Donors for Ribonucleotide Reductase
- 2012
-
Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 287:47
-
Tidskriftsartikel (refereegranskat)abstract
- Bacillus anthracis is the causative agent of anthrax, which is associated with a high mortality rate. Like several medically important bacteria, B. anthracis lacks glutathione but encodes many genes annotated as thioredoxins, thioredoxin reductases, and glutaredoxin-like proteins. We have cloned, expressed, and characterized three potential thioredoxins, two potential thioredoxin reductases, and three glutaredoxin-like proteins. Of these, thioredoxin 1 (Trx1) and NrdH reduced insulin, 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB), and the manganese-containing type Ib ribonucleotide reductase (RNR) from B. anthracis in the presence of NADPH and thioredoxin reductase 1 (TR1), whereas thioredoxin 2 (Trx2) could only reduce DTNB. Potential TR2 was verified as an FAD-containing protein reducible by dithiothreitol but not by NAD(P)H. The recently discovered monothiol bacillithiol did not work as a reductant for RNR, either directly or via any of the redoxins. The catalytic efficiency of Trx1 was 3 and 20 times higher than that of Trx2 and NrdH, respectively, as substrates for TR1. Additionally, the catalytic efficiency of Trx1 as an electron donor for RNR was 7-fold higher than that of NrdH. In extracts of B. anthracis, Trx1 was responsible for almost all of the disulfide reductase activity, whereas Western blots showed that the level of Trx1 was 15 and 60 times higher than that of Trx2 and NrdH, respectively. Our findings demonstrate that the most important general disulfide reductase system in B. anthracis is TR1/Trx1 and that Trx1 is the physiologically relevant electron donor for RNR. This information may provide a basis for the development of novel antimicrobial therapies targeting this severe pathogen.
|
|
| 9. |
- Gustafsson, Tomas N
(författare)
-
Bacterial thioredoxin systems as potential drug targets in novel antimicrobial therapies
- 2013
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Antimicrobial resistance is a big problem in modern medicine. One of the key components in the combat is the characterization of novel drug targets and the development of new classes of compounds targeting them. In the case of the gastric pathogen Helicobacter pylori, increasing resistance necessitates more elaborate and costly treatment-regimes, which cause more side effects than the standard therapy. As for Bacillus anthracis, the causative agent of anthrax, naturally occurring or engineered resistance threatens to compromise the treatment of infections caused by this severe pathogen. The aim of this thesis was to characterize bacterial thioredoxin systems as potential drug targets in bacteria devoid of glutathione. Furthermore, to develop inhibitors that targets these systems. Special emphasis was given to H. pylori as a representative for slow growing, chronic, pathogens and B. anthracis for rapidly growing pathogens giving rise to fulminant disease. Paper nr I: We provided crystal structures of H. pylori thioredoxin reductase in both the oxidized and reduced forms at 1.7 and 1.45Å resolution, respectively. This information could potentially be used for rational design and optimization of inhibitors. Paper nr II: We characterized the thioredoxin system of B. anthracis and concluded that, despite an apparent redundancy, B. anthracis has only one thioredoxin reductase, two thioredoxins and one NrdH-redoxin. Furthermore, thioredoxin 1 was the predominant disulfide reductase and the physiologically relevant electron donor for ribonucleotide reductase. This suggests that the thioredoxin system of B. anthracis could be an attractive drug target. Paper III: We described inhibition of bacterial thioredoxin reductases as a novel antibiotic principle using ebselen. Using pure proteins, we could show that ebselen is a competitive inhibitor of E. coli thioredoxin reductase, acting by binding to the C-terminal active site cysteine. We used various E. coli strains with gene-deletions in the redox systems to show that the absence of glutathione confers sensitivity to ebselen. We also showed that H. pylori and M. tuberculosis, both of which naturally lack glutathione, are sensitive to the drug. Manuscript IV: We studied ebselen and derivatives thereof as inhibitors of B. anthracis thioredoxin reductase and tested their antibacterial activity against B. subtilis. We could show that selected compounds are potent inhibitors of B. anthracis thioredoxin reductase with IC50 values down to 70 nM. Minimal Inhibitory Concentrations (MICs) were down to 0.4 μM (0.12μg/ml) for B. subtilis and compounds had a bacteriocidal mode of action. Based on this, we constructed a structure-activity-relationship and concluded that ebselen and derivatives thereof could potentially be used for the treatment of anthrax. In conclusion, the present thesis deals with the characterization of bacterial thioredoxin systems as potential drug targets - on a biochemical, bacteriological and structural level. The results obtained suggest that bacterial thioredoxin systems are attractive drug targets in bacteria devoid of glutathione and that ebselen might be a viable starting point for drug development. Inhibitors could potentially be used to treat a wide variety of infections including anthrax, gastric ulcers and tuberculosis.
|
|
| 10. |
- Gustafsson, Tomas N., et al.
(författare)
-
Ebselen and analogs as inhibitors of Bacillus anthracis thioredoxin reductase and bactericidal antibacterials targeting Bacillus species, Staphylococcus aureus and Mycobacterium tuberculosis
- 2016
-
Ingår i: Biochimica et Biophysica Acta - General Subjects. - : Elsevier BV. - 0304-4165 .- 1872-8006 .- 0006-3002. ; 1860:6, s. 1265-1271
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Bacillus anthracis is the causative agent of anthrax, a disease associated with a very high mortality rate in its invasive forms. Methods: We studied a number of ebselen analogs as inhibitors of B. anthracis thioredoxin reductase and their antibacterial activity on Bacillus subtilis, Staphylococcus aureus, Bacillus cereus and Mycobacterium tuberculosis. Results: The most potent compounds in the series gave IC50 values down to 70 nM for the pure enzyme and minimal inhibitory concentrations (MICs) down to 0.4 mu M (0.12 mu g/ml) for B. subtilis,1.5 mu M (0.64 mu g/ml) for S. aureus, 2 mu M (0.86 mu g/ml) for B. cereus and 10 mu g/ml for M. tuberculosis. Minimal bactericidal concentrations (MBCs) were found at 1-1.5 times the MIC, indicating a general, class-dependent, bactericidal mode of action. The combined bacteriological and enzymological data were used to construct a preliminary structure-activity-relationship for the benzoisoselenazol class of compounds. When S. aureus and B. subtilis were exposed to ebselen, we were unable to isolate resistant mutants on both solid and in liquid medium suggesting a high resistance barrier. Conclusions: These results suggest that ebselen and analogs thereof could be developed into a novel antibiotic class, useful for the treatment of infections caused by B. anthracis, S. aureus, M. tuberculosis and other clinically important bacteria. Furthermore, the high barrier against resistance development is encouraging for further drug development. General significance: We have characterized the thioredoxin system from B. anthracis as a novel drug target and ebselen and analogs thereof as a potential new class of antibiotics targeting several important human pathogens.
|
|
