The ever unfolding story of cAMP signaling in trypanosomatids: vive la difference!

Kinetoplastids are unicellular, eukaryotic, flagellated protozoans containing the eponymous kinetoplast. Within this order, the family of trypanosomatids are responsible for some of the most serious human diseases, including Chagas disease (Trypanosoma cruzi), sleeping sickness (Trypanosoma brucei spp.), and leishmaniasis (Leishmania spp). Although cAMP is produced during the life cycle stages of these parasites, its signaling pathways are very different from those of mammals. The absence of G-protein-coupled receptors, the presence of structurally different adenylyl cyclases, the paucity of known cAMP effector proteins and the stringent need for regulation of cAMP in the small kinetoplastid cells all suggest a significantly different biochemical pathway and likely cell biology. However, each of the main kinetoplastid parasites express four class 1-type cyclic nucleotide-specific phosphodiesterases (PDEA-D), which have highly similar catalytic domains to that of human PDEs. To date, only TbrPDEB, expressed as two slightly different isoforms TbrPDEB1 and B2, has been found to be essential when ablated. Although the genomes contain reasonably well conserved genes for catalytic and regulatory domains of protein kinase A, these have been shown to have varied structural and functional roles in the different species. Recent discovery of a role of cAMP/AMP metabolism in a quorum-sensing signaling pathway in T. brucei, and the identification of downstream cAMP Response Proteins (CARPs) whose expression levels correlate with sensitivity to PDE inhibitors, suggests a complex signaling cascade. The interplay between the roles of these novel CARPs and the quorum-sensing signaling pathway on cell division and differentiation makes for intriguing cell biology and a new paradigm in cAMP signal transduction, as well as potential targets for trypanosomatid-specific cAMP pathway-based therapeutics

Pyrimidine biosynthesis is not an essential function for trypanosoma brucei bloodstream forms

<p>Background: African trypanosomes are capable of both pyrimidine biosynthesis and salvage of preformed pyrimidines from the host, but it is unknown whether either process is essential to the parasite.</p> <p>Methodology/Principal Findings: Pyrimidine requirements for growth were investigated using strictly pyrimidine-free media, with or without single added pyrimidine sources. Growth rates of wild-type bloodstream form Trypanosoma brucei brucei were unchanged in pyrimidine-free medium. The essentiality of the de novo pyrimidine biosynthesis pathway was studied by knocking out the PYR6-5 locus that produces a fusion product of orotate phosphoribosyltransferase (OPRT) and Orotidine Monophosphate Decarboxylase (OMPDCase). The pyrimidine auxotroph was dependent on a suitable extracellular pyrimidine source. Pyrimidine starvation was rapidly lethal and non-reversible, causing incomplete DNA content in new cells. The phenotype could be rescued by addition of uracil; supplementation with uridine, 2′deoxyuridine, and cytidine allowed a diminished growth rate and density. PYR6-5−/− trypanosomes were more sensitive to pyrimidine antimetabolites and displayed increased uracil transport rates and uridine phosphorylase activity. Pyrimidine auxotrophs were able to infect mice although the infection developed much more slowly than infection with the parental, prototrophic trypanosome line.</p> <p>Conclusions/Significance: Pyrimidine salvage was not an essential function for bloodstream T. b. brucei. However, trypanosomes lacking de novo pyrimidine biosynthesis are completely dependent on an extracellular pyrimidine source, strongly preferring uracil, and display reduced infectivity. As T. brucei are able to salvage sufficient pyrimidines from the host environment, the pyrimidine biosynthesis pathway is not a viable drug target, although any interruption of pyrimidine supply was lethal.</p&gt

Comparing league formats with respect to match importance in Belgian football

Recently, most clubs in the highest Belgian football division have become convinced that the format of their league should be changed. Moreover, the TV station that broadcasts the league is pleading for a more attractive competition. However, the clubs have not been able to agree on a new league format, mainly because they have conflicting interests. In this paper, we compare the current league format, and three other formats that have been considered by the Royal Belgian Football Association. We simulate the course of each of these league formats, based on historical match results. We assume that the attractiveness of a format is determined by the importance of its games; our importance measure for a game is based on the number of teams for which this game can be decisive to reach a given goal. Furthermore, we provide an overview of how each league format aligns with the expectations and interests of each type of club

Light-ion production in the interaction of 96 MeV neutrons with oxygen

Double-differential cross sections for light-ion (p, d, t, He-3 and alpha) production in oxygen, induced by 96 MeV neutrons are reported. Energy spectra are measured at eight laboratory angles from 20 degrees to 160 degrees in steps of 20 degrees. Procedures for data taking and data reduction are presented. Deduced energy-differential and production cross sections are reported. Experimental cross sections are compared to theoretical reaction model calculations and experimental data at lower neutron energies in the literature. The measured proton data agree reasonably well with the results of the model calculations, whereas the agreement for the other particles is less convincing. The measured production cross sections for protons, deuterons, tritons and alpha particles support the trends suggested by data at lower energies.Comment: 21 pages, 13 figures, submitted to Phys. Rev.

Photodissociation of p-process nuclei studied by bremsstrahlung induced activation

A research program has been started to study experimentally the near-threshold photodissociation of nuclides in the chain of cosmic heavy element production with bremsstrahlung from the ELBE accelerator. An important prerequisite for such studies is good knowledge of the bremsstrahlung distribution which was determined by measuring the photodissociation of the deuteron and by comparison with model calculations. First data were obtained for the astrophysically important target nucleus 92-Mo by observing the radioactive decay of the nuclides produced by bremsstrahlung irradiation at end-point energies between 11.8 MeV and 14.0 MeV. The results are compared to recent statistical model calculations.Comment: 6 pages, 8 figures, Proceedings Nuclear Physics in Astrophysics II, May 16-20, 2005, Debrecen, Hungary. The original publication is available at www.eurphysj.or

Quark nova imprint in the extreme supernova explosion SN 2006gy

The extremely luminous supernova 2006gy (SN 2006gy) is among the most energetic ever observed. The peak brightness was 100 times that of a typical supernova and it spent an unheard of 250 days at magnitude -19 or brighter. Efforts to describe SN 2006gy have pushed the boundaries of current supernova theory. In this work we aspire to simultaneously reproduce the photometric and spectroscopic observations of SN 2006gy using a quark nova model. This analysis considers the supernova explosion of a massive star followed days later by the quark nova detonation of a neutron star. We lay out a detailed model of the interaction between the supernova envelope and the quark nova ejecta paying special attention to a mixing region which forms at the inner edge of the supernova envelope. This model is then fit to photometric and spectroscopic observations of SN 2006gy. This QN model naturally describes several features of SN 2006gy including the late stage light curve plateau, the broad H{\alpha} line and the peculiar blue H{\alpha} absorption. We find that a progenitor mass between 20Msun and 40Msun provides ample energy to power SN 2006gy in the context of a QN.Comment: 15 pages, 9 figure

HLA Immunogenotype Determines Persistent Human Papillomavirus Virus Infection in HIV-Infected Patients Receiving Antiretroviral Treatment

A proportion of human immunodeficiency virus (HIV)–infected patients develop persistent, stigmatizing human papillomavirus (HPV)–related cutaneous and genital warts and anogenital (pre)cancer. This is the first study to investigate immunogenetic variations that might account for HPV susceptibility and the largest to date to categorize the HPV types associated with cutaneous warts in HIV-positive patients. The HLA class I and II allele distribution was analyzed in 49 antiretroviral (ART)–treated HIV-positive patients with persistent warts, 42 noninfected controls, and 46 HIV-positive controls. The allele HLA-B*44 was more frequently identified in HIV-positive patients with warts (P = .004); a susceptible haplotype (HLA-B*44, HLA-C*05; P = .001) and protective genes (HLA-DQB1*06; P = .03) may also contribute. Cutaneous wart biopsy specimens from HIV-positive patients harbored common wart types HPV27/57, the unusual wart type HPV7, and an excess of Betapapillomavirus types (P = .002), compared with wart specimens from noninfected controls. These findings suggest that HLA testing might assist in stratifying those patients in whom vaccination should be recommended

Dynamics of tournaments: the soccer case

A random walk-like model is considered to discuss statistical aspects of tournaments. The model is applied to soccer leagues with emphasis on the scores. This competitive system was computationally simulated and the results are compared with empirical data from the English, the German and the Spanish leagues and showed a good agreement with them. The present approach enabled us to characterize a diffusion where the scores are not normally distributed, having a short and asymmetric tail extending towards more positive values. We argue that this non-Gaussian behavior is related with the difference between the teams and with the asymmetry of the scores system. In addition, we compared two tournament systems: the all-play-all and the elimination tournaments.Comment: To appear in EPJ