The Spectrum projection package: improvements in estimating mortality, ART needs, PMTCT impact and uncertainty bounds

BACKGROUND: The approach to national and global estimates of HIV/AIDS used by UNAIDS starts with estimates of adult HIV prevalence prepared from surveillance data using either the Estimation and Projection Package (EPP) or the Workbook. Time trends of prevalence are transferred to Spectrum to estimate the consequences of the HIV/AIDS epidemic, including the number of people living with HIV, new infections, AIDS deaths, AIDS orphans, treatment needs and the impact of treatment on survival. METHODS: The UNAIDS Reference Group on Estimates, Modelling and Projections regularly reviews new data and information needs and recommends updates to the methodology and assumptions used in Spectrum. The latest update to Spectrum was used in the 2007 round of global estimates. RESULTS: Several new features have been added to Spectrum in the past two years. The structure of the population was reorganised to track populations by HIV status and treatment status. Mortality estimates were improved by the adoption of new approaches to estimating non-AIDS mortality by single age, and the use of new information on survival with HIV in non-treated cohorts and on the survival of patients on antiretroviral treatment (ART). A more detailed treatment of mother-to-child transmission of HIV now provides more prophylaxis and infant feeding options. New procedures were implemented to estimate the uncertainty around each of the key outputs. CONCLUSIONS: The latest update to the Spectrum program is intended to incorporate the latest research findings and provide new outputs needed by national and international planners

A Fluctuation Analysis of the Bolocam 1.1mm Lockman Hole Survey

We perform a fluctuation analysis of the 1.1mm Bolocam Lockman Hole Survey, which covers 324 square arcmin to a very uniform point source-filtered RMS noise level of 1.4 mJy/beam. The fluctuation analysis has the significant advantage of utilizing all of the available data. We constrain the number counts in the 1-10 mJy range, and derive significantly tighter constraints than in previous work: the power-law index is 2.7 (+0.18, -0.15), while the amplitude is equal to 1595 (+85,-238) sources per mJy per square degree, or N(>1 mJy) = 940 (+50,-140) sources/square degree (95% confidence). Our results agree extremely well with those derived from the extracted source number counts by Laurent et al (2005). Our derived normalization is about 2.5 times smaller than determined by MAMBO at 1.2mm by Greve et al (2004). However, the uncertainty in the normalization for both data sets is dominated by the systematic (i.e., absolute flux calibration) rather than statistical errors; within these uncertainties, our results are in agreement. We estimate that about 7% of the 1.1mm background has been resolved at 1 mJy.Comment: To appear in the Astrophysical Journal; 22 pages, 9 figure

DNA binding shifts the redox potential of the transcription factor SoxR

Electrochemistry measurements on DNA-modified electrodes are used to probe the effects of binding to DNA on the redox potential of SoxR, a transcription factor that contains a [2Fe-2S] cluster and is activated through oxidation. A DNA-bound potential of +200 mV versus NHE (normal hydrogen electrode) is found for SoxR isolated from Escherichia coli and Pseudomonas aeruginosa. This potential value corresponds to a dramatic shift of +490 mV versus values found in the absence of DNA. Using Redmond red as a covalently bound redox reporter affixed above the SoxR binding site, we also see, associated with SoxR binding, an attenuation in the Redmond red signal compared with that for Redmond red attached below the SoxR binding site. This observation is consistent with a SoxR-binding-induced structural distortion in the DNA base stack that inhibits DNA-mediated charge transport to the Redmond red probe. The dramatic shift in potential for DNA-bound SoxR compared with the free form is thus reconciled based on a high-energy conformational change in the SoxR–DNA complex. The substantial positive shift in potential for DNA-bound SoxR furthermore indicates that, in the reducing intracellular environment, DNA-bound SoxR is primarily in the reduced form; the activation of DNA-bound SoxR would then be limited to strong oxidants, making SoxR an effective sensor for oxidative stress. These results more generally underscore the importance of using DNA electrochemistry to determine DNA-bound potentials for redox-sensitive transcription factors because such binding can dramatically affect this key protein property

Irradiation of the secondary star in X-ray Nova Scorpii 1994 (=GRO J1655--40)

We have obtained intermediate resolution optical spectra of the black-hole candidate Nova Sco 1994 in June 1996, when the source was in an X-ray/optical active state (R~15.05). We measure the radial velocity curve of the secondary star and obtain a semi-amplitude of 279+/-10 km/s; a value which is 30 per cent larger than the value obtained when the source is in quiescence. Our large value for K_2 is consistent with 60 +9,-7 per cent of the secondary star's surface being heated; compared to 35 per cent, which is what one would expect if only the inner face of the secondary star were irradiated. Effects such as irradiation-induced flows on the secondary star may be important in explaining the observed large value for K_2.Comment: 5 pages, 2 figures, accepted by MNRA

Expanding the Repertoire of Natural Product-Inspired Ring Pairs for Molecular Recognition of DNA

A furan amino acid, inspired by the recently discovered proximicin natural products, was incorporated into the scaffold of a DNA-binding hairpin polyamide. While unpaired oligomers of 2,4-disubstituted furan amino acids show poor DNA-binding activity, furan (Fn) carboxamides paired with N-methylpyrrole (Py) and N-methylimidazole (Im) rings demonstrate excellent stabilization of duplex DNA as well as discrimination of noncognate sequences, consistent with function as a Py mimic according to the Py/Im polyamide pairing rules

Detection of the white dwarf and the secondary star in the new SU UMa dwarf nova HS 2219+1824

We report the discovery of a new, non-eclipsing SU UMa-type dwarf nova, HS 2219+1824. Photometry obtained in quiescence (V ≈ 17.5) reveals a double-humped light curve from which we derive an orbital period of 86.2 min. Additional photometry obtained during a superoutburst reaching V 12.0 clearly shows superhumps with a period of 89.05 min. The optical spectrum contains double-peaked Balmer and He I emission lines from the accretion disc as well as broad absorption troughs of Hβ, Hγ, and Hδ from the white dwarf primary star. Modelling of the optical spectrum implies a white dwarf temperature of 13 000 K < ∼ T eff < ∼ 17 000 K, a distance of 180 pc < ∼ d < ∼ 230 pc, and suggests that the spectral type of the donor star is later than M 5. Phase-resolved spectroscopy obtained during quiescence reveals a narrow Hα emission line component which has a radial velocity amplitude and phase consistent with an origin on the secondary star, possibly on the irradiated hemisphere facing the white dwarf. This constitutes the first detection of line emission from the secondary star in a quiescent SU UMa star

The Effects of 11 Yr of CO2 Enrichment on Roots in a Florida Scrub-Oak Ecosystem

Uncertainty surrounds belowground plant responses to rising atmospheric CO2 because roots are difficult to measure, requiring frequent monitoring as a result of fine root dynamics and long-term monitoring as a result of sensitivity to resource availability. We report belowground plant responses of a scrub-oak ecosystem in Florida exposed to 11yr of elevated atmospheric CO2 using open-top chambers. We measured fine root production, turnover and biomass using minirhizotrons, coarse root biomass using ground-penetrating radar and total root biomass using soil cores. Total root biomass was greater in elevated than in ambient plots, and the absolute difference was larger than the difference aboveground. Fine root biomass fluctuated by more than a factor of two, with no unidirectional temporal trend, whereas leaf biomass accumulated monotonically. Strong increases in fine root biomass with elevated CO2 occurred after fire and hurricane disturbance. Leaf biomass also exhibited stronger responses following hurricanes. Responses after fire and hurricanes suggest that disturbance promotes the growth responses of plants to elevated CO2. Increased resource availability associated with disturbance (nutrients, water, space) may facilitate greater responses of roots to elevated CO2. The disappearance of responses in fine roots suggests limits on the capacity of root systems to respond to CO2 enrichment

Comparative genomics of isolates of a pseudomonas aeruginosa epidemic strain associated with chronic lung infections of cystic fibrosis patients

Pseudomonas aeruginosa is the main cause of fatal chronic lung infections among individuals suffering from cystic fibrosis (CF). During the past 15 years, particularly aggressive strains transmitted among CF patients have been identified, initially in Europe and more recently in Canada. The aim of this study was to generate high-quality genome sequences for 7 isolates of the Liverpool epidemic strain (LES) from the United Kingdom and Canada representing different virulence characteristics in order to: (1) associate comparative genomics results with virulence factor variability and (2) identify genomic and/or phenotypic divergence between the two geographical locations. We performed phenotypic characterization of pyoverdine, pyocyanin, motility, biofilm formation, and proteolytic activity. We also assessed the degree of virulence using the Dictyostelium discoideum amoeba model. Comparative genomics analysis revealed at least one large deletion (40-50 kb) in 6 out of the 7 isolates compared to the reference genome of LESB58. These deletions correspond to prophages, which are known to increase the competitiveness of LESB58 in chronic lung infection. We also identified 308 non-synonymous polymorphisms, of which 28 were associated with virulence determinants and 52 with regulatory proteins. At the phenotypic level, isolates showed extensive variability in production of pyocyanin, pyoverdine, proteases and biofilm as well as in swimming motility, while being predominantly avirulent in the amoeba model. Isolates from the two continents were phylogenetically and phenotypically undistinguishable. Most regulatory mutations were isolate-specific and 29% of them were predicted to have high functional impact. Therefore, polymorphism in regulatory genes is likely to be an important basis for phenotypic diversity among LES isolates, which in turn might contribute to this strain's adaptability to varying conditions in the CF lung

Synthesis, antitubercular activity and mechanism of resistance of highly effective thiacetazone analogues

Defining the pharmacological target(s) of currently used drugs and developing new analogues with greater potency are both important aspects of the search for agents that are effective against drug-sensitive and drug-resistant Mycobacterium tuberculosis. Thiacetazone (TAC) is an anti-tubercular drug that was formerly used in conjunction with isoniazid, but removed from the antitubercular chemotherapeutic arsenal due to toxic side effects. However, several recent studies have linked the mechanisms of action of TAC to mycolic acid metabolism and TAC-derived analogues have shown increased potency against M. tuberculosis. To obtain new insights into the molecular mechanisms of TAC resistance, we isolated and analyzed 10 mutants of M. tuberculosis that were highly resistant to TAC. One strain was found to be mutated in the methyltransferase MmaA4 at Gly101, consistent with its lack of oxygenated mycolic acids. All remaining strains harbored missense mutations in either HadA (at Cys61) or HadC (at Val85, Lys157 or Thr123), which are components of the bhydroxyacyl-ACP dehydratase complex that participates in the mycolic acid elongation step. Separately, a library of 31 new TAC analogues was synthesized and evaluated against M. tuberculosis. Two of these compounds, 15 and 16, exhibited minimal inhibitory concentrations 10-fold lower than the parental molecule, and inhibited mycolic acid biosynthesis in a dose-dependent manner. Moreover, overexpression of HadAB HadBC or HadABC in M. tuberculosis led to high level resistance to these compounds, demonstrating that their mode of action is similar to that of TAC. In summary, this study uncovered new mutations associated with TAC resistance and also demonstrated that simple structural optimization of the TAC scaffold was possible and may lead to a new generation of TAC-derived drug candidates for the potential treatment of tuberculosis as mycolic acid inhibitors

The Bolocam Lockman Hole Millimeter-Wave Galaxy Survey: Galaxy Candidates and Number Counts

We present results of a new deep 1.1 mm survey using Bolocam, a millimeter-wavelength bolometer array camera designed for mapping large fields at fast scan rates, without chopping. A map, galaxy candidate list, and derived number counts are presented. This survey encompasses 324 arcmin^2 to an rms noise level (filtered for point sources) of 1.4 mJy/beam and includes the entire regions surveyed by the published 8 mJy 850 micron JCMT SCUBA and 1.2 mm IRAM MAMBO surveys. We reduced the data using a custom software pipeline to remove correlated sky and instrument noise via a principal component analysis. Extensive simulations and jackknife tests were performed to confirm the robustness of our source candidates and estimate the effects of false detections, bias, and completeness. In total, 17 source candidates were detected at a significance > 3.0 sigma, with six expected false detections. Nine candidates are new detections, while eight candidates have coincident SCUBA 850 micron and/or MAMBO 1.2 mm detections. From our observed number counts, we estimate the underlying differential number count distribution of submillimeter galaxies and find it to be in general agreement with previous surveys. Modeling the spectral energy distributions of these submillimeter galaxies after observations of dusty nearby galaxies suggests extreme luminosities of L = 1.0-1.6 x 10^13 L_solar and, if powered by star formation, star formation rates of 500-800 M_solar/yr.Comment: In press (to appear in Astrophysical Journal: 1 May 2005, v624, 1 issue); 21 pages, 15 figures, 3 table