On the Reliability of Cross Correlation Function Lag Determinations in Active Galactic Nuclei

Many AGN exhibit a highly variable luminosity. Some AGN also show a pronounced time delay between variations seen in their optical continuum and in their emission lines. In effect, the emission lines are light echoes of the continuum. This light travel-time delay provides a characteristic radius of the region producing the emission lines. The cross correlation function (CCF) is the standard tool used to measure the time lag between the continuum and line variations. For the few well-sampled AGN, the lag ranges from 1-100 days, depending upon which line is used and the luminosity of the AGN. In the best sampled AGN, NGC 5548, the H_beta lag shows year-to-year changes, ranging from about 8.7 days to about 22.9 days over a span of 8 years. In this paper it is demonstrated that, in the context of AGN variability studies, the lag estimate using the CCF is biased too low and subject to a large variance. Thus the year-to-year changes of the measured lag in NGC 5548 do not necessarily imply changes in the AGN structure. The bias and large variance are consequences of finite duration sampling and the dominance of long timescale trends in the light curves, not due to noise or irregular sampling. Lag estimates can be substantially improved by removing low frequency power from the light curves prior to computing the CCF.Comment: To appear in the PASP, vol 111, 1999 Nov; 37 pages; 10 figure

A cardinal role for cathepsin D in co-ordinating the host-mediated apoptosis of macrophages and killing of pneumococci

The bactericidal function of macrophages against pneumococci is enhanced by their apoptotic demise, which is controlled by the anti-apoptotic protein Mcl-1. Here, we show that lysosomal membrane permeabilization (LMP) and cytosolic translocation of activated cathepsin D occur prior to activation of a mitochondrial pathway of macrophage apoptosis. Pharmacological inhibition or knockout of cathepsin D during pneumococcal infection blocked macrophage apoptosis. As a result of cathepsin D activation, Mcl-1 interacted with its ubiquitin ligase Mule and expression declined. Inhibition of cathepsin D had no effect on early bacterial killing but inhibited the late phase of apoptosis-associated killing of pneumococci in vitro. Mice bearing a cathepsin D-/- hematopoietic system demonstrated reduced macrophage apoptosis in vivo, with decreased clearance of pneumococci and enhanced recruitment of neutrophils to control pulmonary infection. These findings establish an unexpected role for a cathepsin D-mediated lysosomal pathway of apoptosis in pulmonary host defense and underscore the importance of apoptosis-associated microbial killing to macrophage function

Autonomous clustering using rough set theory

This paper proposes a clustering technique that minimises the need for subjective human intervention and is based on elements of rough set theory. The proposed algorithm is unified in its approach to clustering and makes use of both local and global data properties to obtain clustering solutions. It handles single-type and mixed attribute data sets with ease and results from three data sets of single and mixed attribute types are used to illustrate the technique and establish its efficiency

HIV gp120 in the lungs of antiretroviral therapy–treated Individuals impairs alveolar macrophage responses to pneumococci

Rationale People living with HIV (PLWH) are at significantly increased risk of invasive pneumococcal disease, despite long-term antiretroviral therapy (ART). The mechanism explaining this observation remains undefined. Objectives We hypothesized apoptosis-associated microbicidal mechanisms, required to clear intracellular pneumococci that survive initial phagolysosomal killing, are perturbed. Methods Alveolar macrophages (AM) were obtained by bronchoalveolar lavage (BAL) from healthy donors or HIV-1-seropositive donors on long-term ART with undetectable plasma viral load. Monocyte-derived macrophages (MDM) were obtained from healthy donors and infected with HIV-1BaL or treated with gp120. Macrophages were challenged with opsonized serotype 2 Streptococcus pneumoniae and assessed for apoptosis, bactericidal activity, protein expression and mitochondrial reactive oxygen species (mROS). AM phenotyping, ultra-sensitive HIV-1 RNA quantification and gp120 measurement were also performed in BAL. Measurements and Main Results HIV-1BaL infection impaired apoptosis, induction of mROS and pneumococcal killing by MDM. Apoptosis-associated pneumococcal killing was also reduced in AM from ART treated HIV-1-seropositive donors. BAL fluid from these individuals demonstrated persistent lung CD8+ T-cell lymphocytosis, and gp120 or HIV-1 RNA was also detected. Despite this, transcriptional activity in AM freshly isolated from PLWH was broadly similar to healthy volunteers. Instead, gp120 phenocopied the defect in pneumococcal killing in healthy MDM through post-translational modification of Mcl-1, preventing apoptosis induction, caspase activation and increased mROS generation. Moreover gp120 also inhibited mROS dependent pneumococcal killing in MDM. Conclusions. Despite ART, HIV-1, via gp120, drives persisting innate immune defects in AM microbicidal mechanisms, enhancing susceptibility to pneumococcal disease

Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination.

Abstract OBJECTIVE: We characterised the clinical course, treatment and outcomes in 59 patients with relapsing myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination. METHODS: We evaluated clinical phenotypes, annualised relapse rates (ARR) prior and on immunotherapy and Expanded Disability Status Scale (EDSS), in 218 demyelinating episodes from 33 paediatric and 26 adult patients. RESULTS: The most common initial presentation in the cohort was optic neuritis (ON) in 54% (bilateral (BON) 32%, unilateral (UON) 22%), followed by acute disseminated encephalomyelitis (ADEM) (20%), which occurred exclusively in children. ON was the dominant phenotype (UON 35%, BON 19%) of all clinical episodes. 109/226 (48%) MRIs had no brain lesions. Patients were steroid responsive, but 70% of episodes treated with oral prednisone relapsed, particularly at doses <10\u2009mg daily or within 2 months of cessation. Immunotherapy, including maintenance prednisone (P=0.0004), intravenous immunoglobulin, rituximab and mycophenolate, all reduced median ARRs on-treatment. Treatment failure rates were lower in patients on maintenance steroids (5%) compared with non-steroidal maintenance immunotherapy (38%) (P=0.016). 58% of patients experienced residual disability (average follow-up 61 months, visual loss in 24%). Patients with ON were less likely to have sustained disability defined by a final EDSS of 652 (OR 0.15, P=0.032), while those who had any myelitis were more likely to have sustained residual deficits (OR 3.56, P=0.077). CONCLUSION: Relapsing MOG antibody-associated demyelination is strongly associated with ON across all age groups and ADEM in children. Patients are highly responsive to steroids, but vulnerable to relapse on steroid reduction and cessation

Accounting students' IT applicaton skills over a 10-year period

This paper reports on the changing nature of a range of information technology (IT) application skills that students declare on entering an accounting degree over the period from 1996 to 2006. Accounting educators need to be aware of the IT skills students bring with them to university because of the implications this has for learning and teaching within the discipline and the importance of both general and specific IT skills within the practice and craft of accounting. Additionally, IT skills constitute a significant element within the portfolio of employability skills that are increasingly demanded by employers and emphasized within the overall Higher Education (HE) agenda. The analysis of students' reported IT application skills on entry to university, across a range of the most relevant areas of IT use in accounting, suggest that their skills have continued to improve over time. However, there are significant differential patterns of change through the years and within cohorts. The paper addresses the generalizability of these findings and discusses the implications of these factors for accounting educators, including the importance of recognising the differences that are potentially masked by the general increase in skills; the need for further research into the changing nature, and implications, of the gender gap in entrants' IT application skills; and the low levels of entrants' spreadsheet and database skills that are a cause for concern