Development of a topical antibody-based contraceptive: determining Fc functions in the female reproductive tract

The development of antibody-based drugs is continuing to expand at a rapid pace, especially for use at mucosal surfaces to prevent or treat infectious diseases and other conditions. A better understanding of how the Fc region of antibodies interacts with Fc-binding proteins at mucosal sites can inform an optimal design for antibody-based drugs. The Human Contraception Antibody (HCA) is a human IgG1 monoclonal antibody currently under development as a topical vaginal contraceptive. HCA binds to sperm via its Fab domains and causes rapid agglutination with other sperm in close proximity resulting in near complete immobilization of sperm over a wide area. In order to determine whether HCA participates in Fc-mediated functions in the female reproductive tract (FRT), we assessed the activity of HCA and engineered variants in three assays of Fc-mediated functions: complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and mucus trapping. The physiological relevance of CDC was confirmed by characterizing complement levels and activity in cervical mucus. Finally, we described the activity of a novel Fc receptor expressed by vaginal epithelium. With complement, HCA significantly reduced sperm motility and increased the number of lysed sperm via CDC. Additionally, human cervical mucus was found to have sufficient levels of complement to induce the classical complement cascade. HCA-opsonized sperm associated with macrophages and were phagocytosed via ADCP. HCA also trapped sperm in ovulatory human cervical mucus, significantly reducing their progression. Variants of HCA with mutated or obstructed Fc domains had decreased abilities to perform these Fc functions, while multivalent IgM-like and IgA variants of HCA were very effective in both sperm agglutination and Fc assays. We also investigated the novel expression of Fc alpha RI (CD89) by human vaginal epithelium and provide evidence that this Fc receptor may transport IgA through the mucosa. Basal application of IgA resulted in IgA in apical supernatants which was significantly reduced following treatment with a CD89 blocker. In summary, these studies provide an improved understanding of the possible Fc functions of HCA and other antibodies in the human FRT, including interactions with complement, cervical mucus, and Fc receptors. Determining which interactions can occur in vivo and which are desired for a specific indication can inform the design of mucosally applied antibody-based drugs like HCA, a much-needed novel contraceptive antibody

Capital allocation for credit portfolios with kernel estimators

Determining contributions by sub-portfolios or single exposures to portfolio-wide economic capital for credit risk is an important risk measurement task. Often economic capital is measured as Value-at-Risk (VaR) of the portfolio loss distribution. For many of the credit portfolio risk models used in practice, the VaR contributions then have to be estimated from Monte Carlo samples. In the context of a partly continuous loss distribution (i.e. continuous except for a positive point mass on zero), we investigate how to combine kernel estimation methods with importance sampling to achieve more efficient (i.e. less volatile) estimation of VaR contributions.Comment: 22 pages, 12 tables, 1 figure, some amendment

Stochastic Budget Optimization in Internet Advertising

Internet advertising is a sophisticated game in which the many advertisers "play" to optimize their return on investment. There are many "targets" for the advertisements, and each "target" has a collection of games with a potentially different set of players involved. In this paper, we study the problem of how advertisers allocate their budget across these "targets". In particular, we focus on formulating their best response strategy as an optimization problem. Advertisers have a set of keywords ("targets") and some stochastic information about the future, namely a probability distribution over scenarios of cost vs click combinations. This summarizes the potential states of the world assuming that the strategies of other players are fixed. Then, the best response can be abstracted as stochastic budget optimization problems to figure out how to spread a given budget across these keywords to maximize the expected number of clicks. We present the first known non-trivial poly-logarithmic approximation for these problems as well as the first known hardness results of getting better than logarithmic approximation ratios in the various parameters involved. We also identify several special cases of these problems of practical interest, such as with fixed number of scenarios or with polynomial-sized parameters related to cost, which are solvable either in polynomial time or with improved approximation ratios. Stochastic budget optimization with scenarios has sophisticated technical structure. Our approximation and hardness results come from relating these problems to a special type of (0/1, bipartite) quadratic programs inherent in them. Our research answers some open problems raised by the authors in (Stochastic Models for Budget Optimization in Search-Based Advertising, Algorithmica, 58 (4), 1022-1044, 2010).Comment: FINAL versio

Non-smooth optimization methods for computation of the conditional value-at-risk and portfolio optimization

We examine numerical performance of various methods of calculation of the Conditional Value-at-risk (CVaR), and portfolio optimization with respect to this risk measure. We concentrate on the method proposed by Rockafellar and Uryasev in (Rockafellar, R.T. and Uryasev, S., 2000, Optimization of conditional value-at-risk. Journal of Risk, 2, 21-41), which converts this problem to that of convex optimization. We compare the use of linear programming techniques against a non-smooth optimization method of the discrete gradient, and establish the supremacy of the latter. We show that non-smooth optimization can be used efficiently for large portfolio optimization, and also examine parallel execution of this method on computer clusters.<br /

Algorithm Engineering in Robust Optimization

Robust optimization is a young and emerging field of research having received a considerable increase of interest over the last decade. In this paper, we argue that the the algorithm engineering methodology fits very well to the field of robust optimization and yields a rewarding new perspective on both the current state of research and open research directions. To this end we go through the algorithm engineering cycle of design and analysis of concepts, development and implementation of algorithms, and theoretical and experimental evaluation. We show that many ideas of algorithm engineering have already been applied in publications on robust optimization. Most work on robust optimization is devoted to analysis of the concepts and the development of algorithms, some papers deal with the evaluation of a particular concept in case studies, and work on comparison of concepts just starts. What is still a drawback in many papers on robustness is the missing link to include the results of the experiments again in the design

Treatment of rising damp in historical buildings: wall base ventilation

Intervention in older buildings increasingly requires extensive and objective knowledge of what one will be working with. The multifaceted aspect of work carried out on buildings tends to encompass a growing number of specialities, with marked emphasis on learning the causes of many of the problems that affect these buildings and the possible treatments that can solve them. Moisture transfer in walls of old buildings, which are in direct contact with the ground, leads to a migration of soluble salts responsible for many building pathologies.http://www.sciencedirect.com/science/article/B6V23-4H7T0H7-1/1/f5e8a4ec173c5dadf120770678facf4

Visions of and through the *group in early twentieth-century French novels

The first half of the twentieth century saw in France the publication of a proliferation of novels in which individual heroes were supplanted by groups around which descriptions and intrigue were centered. This study examines some of the reasons behind this new literary development and the resulting subjects treated and narrative techniques employed to further the representation of the group. A cross-section of novels published between 1911 and 1949 are analyzed in terms of the group structures presented, the themes developed and the means of representation. The time period saw much interest in collectives, with the development of the field of sociology and political ideologies such as Marxism; movements in psychology and philosophy also examined the role of society in relationship to the individual. The novels fell into three categories: groups formed from a geo-political community, collectives newly established, and groups of soldiers. Invariably, the plot is motivated by some kind of crisis. In each case, a focus on a group was found to allow a somehow “better” representation of events, whether by indicating the need for solidarity, demonstrating the dangers of association with evil, advancing the theory of fleeting unions through a group “soul” or exposing the extent of desolation provoked by imprisonment or war. Focus on a group led to literary experimentation such as simultaneism, juxtaposition, unattributed dialogue, ambiguous use of pronouns, multiple focalizations and an abundance of first person plural pronouns, as well as ‘on’, ‘ils’ and collective nouns. Group centered novels were thus a means of communicating a message particular to the era and the source of narrative innovation which has carried over into later novels

Rastersondenmikroskop mit einem Array von Einzelelektronentransistoren als Sonden zur Potentialvermessung eines zweidimensionalen Elektronensystems unter Quanten Hall Bedingungen unter 40 milli-Kelvin Temperatur

In this thesis a newly built scanning single-electron transistor microscope in a highly vibration damped laboratory environment is presented. The main purpose of this setup is to obtain electrostatic potential distributions of surface near electron systems. Additionally, the microscope is sensitive to changes in capacitance, charge, contact potential, and temperature. One unique feature of this setup is the one-dimensional array of up to eight probing tips with a fixed spacing of 4 µm between them. Furthermore, the combination of its almost negligible influence on the sample while scanning over the surface, as well as its working temperature of less than 40 milli-Kelvin distinguishes it from the few other microscopes of its kind. At the beginning of the thesis the description of the microscope setup and functionality with an extensive characterization can be found. Moreover, electrostatic simulations based on the finite element method are presented to explain and understand measurement data obtained for the tip-sample approach and compensation. In the last sections the calibration technique used to measure Hall potential distributions is explained and the necessary set of measurements for the case of the integer filling factor four is shown. As a prospect for future measurements this microscope allows to obtain Hall potential distributions of samples under fractional quantum Hall conditions. In addition, the microscope is capable of intentionally disturbing the investigated electron system locally and simultaneously determining its response with the neighboring probing tips