Analysis of Linear Antibody Epitopes on Factor H and CFHR1 Using Sera of Patients with Autoimmune Atypical Hemolytic Uremic Syndrome

Introduction: In autoimmune atypical hemolytic uremic syndrome (aHUS), the complement regulator factor H (FH) is blocked by FH autoantibodies, while 90% of the patients carry a homozygous deletion of its homolog complement FH-related protein 1 (CFHR1). The functional consequence of FH-blockade is widely established; however, the molecular basis of autoantibody binding and the role of CFHR1 deficiency in disease pathogenesis are still unknown. We performed epitope mapping of FH to provide structural insight in the autoantibody recruitment on FH and potentially CFHR1. Methods: Eight anti-FH positive aHUS patients were enrolled in this study. With overlapping synthetic FH and CFHR1 peptides, we located the amino acids (aa) involved in binding of acute and convalescence stage autoantibodies. We confirmed the location of the mapped epitopes using recombinant FH domains 19-20 that carried single-aa substitutions at the suspected antibody binding sites in three of our patients. Location of the linear epitopes and the introduced point mutations was visualized using crystal structures of the corresponding domains of FH and CFHR1. Results: We identified three linear epitopes on FH (aa1157-1171; aa1177-1191; and aa1207-1226) and one on CFHR1 (aa276-290) that are recognized both in the acute and convalescence stages of aHUS. We observed a similar extent of autoantibody binding to the aHUS-specific epitope aa1177-1191 on FH and aa276-290 on CFHR1, despite seven of our patients being deficient for CFHR1. Epitope mapping with the domain constructs validated the location of the linear epitopes on FH with a distinct autoantibody binding motif within aa1183-1198 in line with published observations. Summary: According to the results, the linear epitopes we identified are located close to each other on the crystal structure of FH domains 19-20. This tertiary configuration contains the amino acids reported to be involved in C3b and sialic acid binding on the regulator, which may explain the functional deficiency of FH in the presence of auto antibodies. The data we provide identify the exact structures involved in autoantibody recruitment on FH and confirm the presence of an autoantibody binding epitope on CFHR1.Peer reviewe

Essays on Peer Effects

<p>This dissertation considers the relationship between peer and individual student interaction. The central finding is that self reported friends play a crucial role in individual behaviors, a role that is more significant than other students in their school. Also, using the network of friendships within a school it is possible to construct new peer effect measures and account for endogenous peer group formation. It is however important to distinguish these peer measures from unobserved individual characteristics that may also influence behavior.</p><p>The first chapter examines the effect of potentially misidentifying the reference group on peer effect estimates. The differential impact of school, grade and friend level peer effects on student decisions to smoke and drink are calculated. Friendship nominations come from the Add Health dataset, where students can list up to 10 friends from the school. The bias due to endogenous peer group formation and simulteneity are considered using various instrumenting strategies. Peer effects are found to be large and significant at the friends level for both delinquency variables. It is possible to show that misidentifying the peer group can result in peer effect estimates that are understated by as much as 40\%.</p><p>The second chapter of the dissertation further examines the role of peer interactions, this time considering the effect of popularity on student academic achievement. Recent work has found a strong positive relationship between these variables. In this chapter I ascertain the robustness of these previous findings to controls for unobserved student heterogeneity using and instrumenting technique and a structural model. The results indicate that popularity influences academic achievement positively in the baseline model. However, instrumenting for popularity or including measures of unobserved student characteristics results in a large drop in the effect of popularity, and leads to a significantly negative coefficient in the majority of cases. Interestingly, popularity influences future earnings and attitudes positively, where this effect is robust to the inclusion of unobserved type. Policy simulations where students are redistributed based on race or income indicate that the predicted number of friendships and popularity fall but academic achievement increases. Since student popularity increases happiness and earnings, the overall effect of the redistribution policies have to be considered before implementation.</p>Dissertatio

Single Women\u27s Labor Supply Elasticities: Trends and Policy Implications

This paper uses CPS data to examine changes in single women’s labor supply elas­ticities in recent decades. Specifically, the authors investigate trends in how single women’s hours of work and labor force participation rates responded to both wages and income over the years 1979–2003. Results from the base specification suggest that over the observation period, hours wage elasticities decreased by 82%, participation wage elasticities by 36%, and participation income elasticities by 57%. These results imply that changes in tax policy had a much larger effect on the labor supply and labor force participation behavior of women in this subpopulation in the early 1980s than in recent years

A review of Stata commands for fixed-effects estimation in normal linear models

Availability of large multilevel longitudinal databases in various fields of research, including labor economics (with workers and firms observed over time) and education (with students, teachers, and schools observed over time), has increased the application of models with one level or multiple levels of fixed effects (for example, teacher and student effects). There has been a corresponding rapid development of Stata commands designed for fitting these types of models. The commands parameterize the fixed-effects portions of models differently. In cases where estimates of the fixed-effects parameters are of interest, it is critical to understand precisely what parameters are being estimated by different commands. In this article, we catalog the estimates of reported fixed effects provided by different commands for several canonical cases of both one-level and two-level fixed-effects models. We also discuss issues regarding computational efficiency and standard-error estimation