Can the UNAIDS modes of transmission model be improved? A comparison of the original and revised model projections using data from a setting in west Africa.

OBJECTIVE: The UNAIDS modes of transmission model (MoT) is a user-friendly model, developed to predict the distribution of new HIV infections among different subgroups. The model has been used in 29 countries to guide interventions. However, there is the risk that the simplifications inherent in the MoT produce misleading findings. Using input data from Nigeria, we compare projections from the MoT with those from a revised model that incorporates additional heterogeneity. METHODS: We revised the MoT to explicitly incorporate brothel and street-based sex-work, transactional sex, and HIV-discordant couples. Both models were parameterized using behavioural and epidemiological data from Cross River State, Nigeria. Model projections were compared, and the robustness of the revised model projections to different model assumptions, was investigated. RESULTS: The original MoT predicts 21% of new infections occur in most-at-risk-populations (MARPs), compared with 45% (40-75%, 95% Crl) once additional heterogeneity and updated parameterization is incorporated. Discordant couples, a subgroup previously not explicitly modelled, are predicted to contribute a third of new HIV infections. In addition, the new findings suggest that women engaging in transactional sex may be an important but previously less recognized risk group, with 16% of infections occurring in this subgroup. CONCLUSION: The MoT is an accessible model that can inform intervention priorities. However, the current model may be potentially misleading, with our comparisons in Nigeria suggesting that the model lacks resolution, making it challenging for the user to correctly interpret the nature of the epidemic. Our findings highlight the need for a formal review of the MoT

Testing the Hidden Local Symmetry Model

The aim of this thesis is to test the recently proposed effective Lagrangian for pi, rho and gamma physics, called the Hidden Local Symmetry (HLS) model, against experimental data on the process gammagamma→rhorho. To this end Chapter 1 is a general introduction, motivating the interest in studying the HLS model in particular and pointing out its relation to composite models of Higgs and W/Z bosons. It is noted that there is a crucial sector of this model that has, until now, remained untested. It is observed that this untested sector can be probed by comparing the predictions of the model with the well established data on gammagamma→rhorho; which in itself is an interesting process and in need of better theoretical understanding. Chapter 2 is an introduction to the HLS model and in section (i) the construction of the model Lagrangian is presented. The HLS model has an arbitrary parameter 'a', it is shown in section (ii) that so far the attempts to determine 'a' by some "underlying" symmetry principle fail when confronted with phenomenology. In section (iii) the pivotal role of the HLS model of vector mesons in the Skyrmion picture of baryon physics is explained. Section (iv) summarises the chapter and underlines the need to test the HLS model fully. Chapter 3 is a summary of the current experimental and theoretical status of gammagamma→V1V2 physics (V1,2=rho, o, k*, ϕ). It is emphasised that there is still room for a "conventional explanation" of the process gammagamma→rhorho. Thus the second strand of the thesis is testing the possibility of the HLS model explaining the data on gammagamma-rhorho. Chapter 4 is the first order, or tree-level, calculation of gammagamma→rhorho in the HLS model, it is found to be in disagreement with experimental data. Which leads us to consider in chapter 5 the motivation for a one loop calculation of gammagamma→rhorho; the approach taken in estimating the loop corrections, in the spirit of chiral perturbation theory, is outlined. In chapter 6 the loop diagram calculation for gammagamma→pp is presented, the results indicate that the perturbative expansion fails. It is thus necessary to check this result before proceeding any further with the loop calculation. The rho+rho- scattering amplitudes in the HLS model are shown to violate unitarity in chapter 7, this is an independent check on the loop diagram 'calculation in chapter 6. In chapter 8 it is concluded that the HLS model fails to describe gammagamma→rhorho perturbatively. The discussion of the results of this thesis includes an outline of several interesting possibilities for future work

SUMO chain formation is required for response to replication arrest in S. pombe

SUMO is a ubiquitin-like protein that is post-translationally attached to one or more lysine residues on target proteins. Despite having only 18% sequence identity with ubiquitin, SUMO contains the conserved betabetaalphabetabetaalphabeta fold present in ubiquitin. However, SUMO differs from ubiquitin in having an extended N-terminus. In S. pombe the N-terminus of SUMO/Pmt3 is significantly longer than those of SUMO in S. cerevisiae, human and Drosophila. Here we investigate the role of this N-terminal region. We have used two dimensional gel electrophoresis to demonstrate that S. pombe SUMO/Pmt3 is phosphorylated, and that this occurs on serine residues at the extreme N-terminus of the protein. Mutation of these residues (in pmt3-1) results in a dramatic reduction in both the levels of high Mr SUMO-containing species and of total SUMO/Pmt3, indicating that phosphorylation of SUMO/Pmt3 is required for its stability. Despite the significant reduction in high Mr SUMO-containing species, pmt3-1 cells do not display an aberrant cell morphology or sensitivity to genotoxins or stress. Additionally, we demonstrate that two lysine residues in the N-terminus of S. pombe SUMO/Pmt3 (K14 and K30) can act as acceptor sites for SUMO chain formation in vitro. Inability to form SUMO chains results in aberrant cell and nuclear morphologies, including stretched and fragmented chromatin. SUMO chain mutants are sensitive to the DNA synthesis inhibitor, hydroxyurea (HU), but not to other genotoxins, such as UV, MMS or CPT. This implies a role for SUMO chains in the response to replication arrest in S. pomb

Double-strand break repair and homologous recombination in Schizosaccharomyces pombe

In recent years our understanding of double strand break repair and homologous recombination in Schizosaccharomyces pombe has increased significantly, and the identification of novel pathways and genes with homologues in higher eukaryotes has increased its value as a model organisms for double strand break repair. We will review the S. pombe literature on double strand break repair, mainly focussing on homologous recombination in mitotic cells

Involvement of Schizosaccharomyces pombe rrp1+ and rrp2+ in the Srs2- and Swi5/Sfr1-dependent pathway in response to DNA damage and replication inhibition

Previously we identified Rrp1 and Rrp2 as two proteins required for the Sfr1/Swi5-dependent branch of homologous recombination (HR) in Schizosaccharomyces pombe. Here we use a yeast two-hybrid approach to demonstrate that Rrp1 and Rrp2 can interact with each other and with Swi5, an HR mediator protein. Rrp1 and Rrp2 form co-localizing methyl methanesulphonate–induced foci in nuclei, further suggesting they function as a complex. To place the Rrp1/2 proteins more accurately within HR sub-pathways, we carried out extensive epistasis analysis between mutants defining Rrp1/2, Rad51 (recombinase), Swi5 and Rad57 (HR-mediators) plus the anti-recombinogenic helicases Srs2 and Rqh1. We confirm that Rrp1 and Rrp2 act together with Srs2 and Swi5 and independently of Rad57 and show that Rqh1 also acts independently of Rrp1/2. Mutants devoid of Srs2 are characterized by elevated recombination frequency with a concomitant increase in the percentage of conversion-type recombinants. Strains devoid of Rrp1 or Rrp2 did not show a change in HR frequency, but the number of conversion-type recombinants was increased, suggesting a possible function for Rrp1/2 with Srs2 in counteracting Rad51 activity. Our data allow us to propose a model placing Rrp1 and Rrp2 functioning together with Swi5 and Srs2 in a synthesis-dependent strand annealing HR repair pathway

Slx8 removes Pli1-dependent protein-SUMO conjugates including SUMOylated Topoisomerase I to promote genome stability

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