Parameter Estimation and Confidence Regions in the Method of Light Curve Simulations for the Analysis of Power Density Spectra

The Method of Light Curve Simulations is a tool that has been applied to X-ray monitoring observations of Active Galactic Nuclei (AGN) for the characterization of the Power Density Spectrum (PDS) of temporal variability and measurement of associated break frequencies (which appear to be an important diagnostic for the mass of the black hole in these systems as well as their accretion state). It relies on a model for the PDS that is fit to the observed data. The determination of confidence regions on the fitted model parameters is of particular importance, and we show how the Neyman construction based on distributions of estimates may be implemented in the context of light curve simulations. We believe that this procedure offers advantages over the method used in earlier reports on PDS model fits, not least with respect to the correspondence between the size of the confidence region and the precision with which the data constrain the values of the model parameters. We plan to apply the new procedure to existing RXTE and XMM observations of Seyfert I galaxies as well as RXTE observations of the Seyfert II galaxy NGC 4945.Comment: 9 pages, 2 figures, accepted for publication in Ap

Model of Transcriptional Activation by MarA in Escherichia coli

We have developed a mathematical model of transcriptional activation by MarA in Escherichia coli, and used the model to analyze measurements of MarA-dependent activity of the marRAB, sodA, and micF promoters in mar-rob- cells. The model rationalizes an unexpected poor correlation between the mid-point of in vivo promoter activity profiles and in vitro equilibrium constants for MarA binding to promoter sequences. Analysis of the promoter activity data using the model yielded the following predictions regarding activation mechanisms: (1) MarA activation of the marRAB, sodA, and micF promoters involves a net acceleration of the kinetics of transitions after RNA polymerase binding, up to and including promoter escape and message elongation; (2) RNA polymerase binds to these promoters with nearly unit occupancy in the absence of MarA, making recruitment of polymerase an insignificant factor in activation of these promoters; and (3) instead of recruitment, activation of the micF promoter might involve a repulsion of polymerase combined with a large acceleration of the kinetics of polymerase activity. These predictions are consistent with published chromatin immunoprecipitation assays of interactions between polymerase and the E. coli chromosome. A lack of recruitment in transcriptional activation represents an exception to the textbook description of activation of bacterial sigma-70 promoters. However, use of accelerated polymerase kinetics instead of recruitment might confer a competitive advantage to E. coli by decreasing latency in gene regulation.Comment: 30 pages, 2 figure

High Temporal Resolution XMM Monitoring of PKS 2155-304

The bright, strongly variable BL Lac object PKS 2155-304 was observed by XMM for two essentially uninterrupted periods of ~11 and 16 hr on 30-31 May 2000. The strongest variations occurred in the highest energy bands. After scaling for this effect, the three softest bands (0.1-1.7 keV) showed strong correlation with no measurable lag to reliable limits of \tau \ls 0.3 hr. However, the hardest band (~3 keV) was less well-correlated with the other three, especially on short time scales, showing deviations of ~10-20% in ~1 hr although, again, no significant interband lag was detected. This result and examination of previous ASCA and BeppoSAX cross-correlation functions suggest that previous claims of soft lags on time scales of 0.3-4 hr could well be an artifact of periodic interruptions due to Earth-occultation every 1.6 hr. Previous determinations of the magnetic field/bulk Lorentz factor were therefore premature, as these data provide only a lower limit of B \gamma^{1/3} \gs 2.5 G. The hardest band encompasses the spectral region above the high-energy break; its enhanced variability could be indicating that the break energy of the synchrotron spectrum, and therefore of the underlying electron energy distribution, changes independently of the lower energies.Comment: 13 pages, 3 figures, accepted by Ap

Long-term effects of intermittent IL-2 in HIV infection: extended follow-up of the INSIGHT STALWART Study

BACKGROUND The Study of Aldesleukin with and without Antiretroviral Therapy (STALWART) was designed to evaluate whether intermittent IL-2 alone or with peri-cycle ART increased CD4+ cell counts (and so delayed initiation of ART) in HIV infected individuals having ≥ 300 CD4+ cells/mm(3) compared to untreated controls. When the results of two large clinical trials, ESPRIT and SILCAAT, showed no clinical benefit from IL-2 therapy, IL-2 administration was halted in STALWART. Because IL-2 recipients in STALWART experienced a greater number of opportunistic disease (OD) or death and adverse events (AEs), participants were asked to consent to an extended follow-up phase in order to assess persistence of IL-2 effects. METHODOLOGY Participants in this study were followed for clinical events and AEs every 4 months for 24 months. Unadjusted Cox proportional hazards models were used to summarize death, death or first OD event, and first grade 3 or 4 AE. PRINCIPAL FINDINGS A total of 267 persons were enrolled in STALWART (176 randomized to the IL-2 arms and 91 to the no therapy arm); 142 individuals in the IL-2 group and 80 controls agreed to enter the extended follow-up study. Initiation of continuous ART was delayed in the IL-2 groups, but once started, resulted in similar CD4+ cell and viral load responses compared to controls. The hazard ratios (95% CI) for IL-2 versus control during the extension phase for death or OD, grade 3 or 4 AE, and grade 4 AE were 1.45 (0.38, 5.45), 0.43 (0.24, 1.63) and 0.20 (0.04, 1.03), respectively. The hazard ratios for the AE outcomes were significantly lower during the extension than during the main study. CONCLUSIONS Adverse events associated with IL-2 cycling did not persist upon discontinuation of IL-2. The use of IL-2 did not impact the subsequent response to initiation of cART

Absence of HIV-1 Evolution in the Gut-Associated Lymphoid Tissue from Patients on Combination Antiviral Therapy Initiated during Primary Infection

Mucosal mononuclear (MMC) CCR5+CD4+ T cells of the gastrointestinal (GI) tract are selectively infected and depleted during acute HIV-1 infection. Despite early initiation of combination antiretroviral therapy (cART), gut-associated lymphoid tissue (GALT) CD4+ T cell depletion and activation persist in the majority of HIV-1 positive individuals studied. This may result from ongoing HIV-1 replication and T-cell activation despite effective cART. We hypothesized that ongoing viral replication in the GI tract during cART would result in measurable viral evolution, with divergent populations emerging over time. Subjects treated during early HIV-1 infection underwent phlebotomy and flexible sigmoidoscopy with biopsies prior to and 15–24 months post initiation of cART. At the 2nd biopsy, three GALT phenotypes were noted, characterized by high, intermediate and low levels of immune activation. A representative case from each phenotype was analyzed. Each subject had plasma HIV-1 RNA levels <50 copies/ml at 2nd GI biopsy and CD4+ T cell reconstitution in the peripheral blood. Single genome amplification of full-length HIV-1 envelope was performed for each subject pre- and post-initiation of cART in GALT and PBMC. A total of 280 confirmed single genome sequences (SGS) were analyzed for experimental cases. For each subject, maximum likelihood phylogenetic trees derived from molecular sequence data showed no evidence of evolved forms in the GALT over the study period. During treatment, HIV-1 envelope diversity in GALT-derived SGS did not increase and post-treatment GALT-derived SGS showed no substantial genetic divergence from pre-treatment sequences within transmitted groups. Similar results were obtained from PBMC-derived SGS. Our results reveal that initiation of cART during acute/early HIV-1 infection can result in the interruption of measurable viral evolution in the GALT, suggesting the absence of de-novo rounds of HIV-1 replication in this compartment during suppressive cART

Searching for the Kuhnian moment : the Black-Scholes-Merton formula and the evolution of modern finance theory

The Black-Scholes-Merton formula has been put to widespread use by options traders because it provides a means of calculating the theoretically 'correct' price of stock options. Traders can therefore see whether the market price of stock options undervalues or overvalues them compared with their hypothetical Black-Scholes-Merton price, before choosing to buy or sell options accordingly. As a consequence of this close relationship between options pricing theory and options pricing practice, a strong performativity loop was activated, whereby market prices quickly converged on the hypothetical Black-Scholes-Merton prices following the dissemination of the formula. The theory has therefore had significant real-world effects, but how should we characterize the initial instinct to derive the theory from a philosophy of science perspective? The two books under review suggest that a Kuhnian reading of the advancement of scientific knowledge might well be the most appropriate. But, on closer inspection, it becomes clear that the publication of the Black-Scholes-Merton formula should not be seen as a Kuhnian moment with paradigm-shaping attributes. It is shown that, at most, the formula acts as an important exemplar which, via its use in the training of options pricing theorists and options pricing practitioners, reinforces the entrenchment of finance theory within the orthodox economics worldview

Virological and Immunological Effects of Combination Antiretroviral Therapy with Zidovudine, Lamivudine, and Indinavir during Primary Human Immunodeficiency Virus Type 1 Infection

Forty-seven patients presenting with primary human immunodeficiency virus (HIV) infection were treated with zidovudine 200 mg 3 times a day, lamivudine 150 mg 2 times a day, and indinavir 800 mg 3 times a day for 1 year. From a mean pretreatment viral RNA level of 4.93 log10 copies/mL, the proportions of patients having <500 copies/mL at 24 and 52 weeks were 92.0% and 89.2%, respectively. For the 35 patients with data available at 24 and 52 weeks, the corresponding proportions for the <50 copies/mL analysis were 86.6% and 79.3%, respectively. The change in virus load was −2.19 and −2.41 log10 copies/mL at weeks 8 and 52, respectively. CD4 cell counts increased, from a mean of 546 cells/mm3, by 142 cells/mm3 at week 24 and by 210 cells/mm3 at week 52. Three patients discontinued the study because of drug-related toxicity. Six (12.8%) patients had adverse experiences associated with nephrolithiasis. Combination therapy with zidovudine, lamivudine, and indinavir during primary HIV infection results in a profound and sustained reduction in virus load with concurrent recovery of the CD4 cell populatio