For reproducibility, we need the methods behind the data

2018/19 eLife Ambassadors progra

Modeling reduction of pandemic influenza using pharmaceutical and non pharmaceutical interventions in a heterogeneous population

Thesis (Ph. D.)--Massachusetts Institute of Technology, Sloan School of Management, Operations Research Center, 2012.Cataloged from PDF version of thesis.Includes bibliographical references.In an event of a pandemic influenza outbreak such as the great "Spanish Flu" of 1918 and the more recent 2009-2010 H1N1 "Swine Flu" scare, pharmaceutical as well as non-pharmaceutical resources are limited in availability and effectiveness. In this thesis we apply OR methods to evaluate the effectiveness of such resources and the strategies for reducing the number of infections resulting from an outbreak. In the first half of this work, we focus on epidemiological analysis of influenza modeling in a heterogeneous population. The majority of existing epidemiological literature models influenza spread in a statistically homogeneous population, but the model-based inclusion of heterogeneity by contact rate, susceptibility, and infectivity introduces significant effects on disease progression. We introduce a new discrete-time influenza outbreak model for a heterogeneous population and use it to describe the changes in a population's flu-related characteristics over time. This information allows us to evaluate the effectiveness of different vaccine targeting techniques in achieving herd immunity, that is, the point at which there is no further growth in new infections. In the second half of this work we switch to a practical application of OR methods in a pandemic situation. We evaluate the effectiveness of vaccines administered to US states during the 2009-2010 H1N1 pandemic. Since the US is geographically diverse and large, the outbreak progressed at different rates and started at different times in each individual state. We discuss dynamic, multi-regional, vaccine allocation schemes for large geographical entities that take into account the different conditions of the epidemic in each region and maximize the total effect of available vaccines. In addition, we discuss effective strategies for combining vaccines with non-pharmaceutical interventions such as hand-washing and public awareness campaigns to decrease the strain of an outbreak on the population.by Anna Teytelman.Ph.D

Co-Evolution of Transcriptional Silencing Proteins and the DNA Elements Specifying Their Assembly

Co-evolution of transcriptional regulatory proteins and their sites of action has been often hypothesized but rarely demonstrated. Here we provide experimental evidence of such co-evolution in yeast silent chromatin, a finding that emerged from studies of hybrids formed between two closely related Saccharomyces species. A unidirectional silencing incompatibility between S. cerevisiae and S. bayanus led to a key discovery: asymmetrical complementation of divergent orthologs of the silent chromatin component Sir4. In S. cerevisiae/S. bayanus interspecies hybrids, ChIP-Seq analysis revealed a restriction against S. cerevisiae Sir4 associating with most S. bayanus silenced regions; in contrast, S. bayanus Sir4 associated with S. cerevisiae silenced loci to an even greater degree than did S. cerevisiae's own Sir4. Functional changes in silencer sequences paralleled changes in Sir4 sequence and a reduction in Sir1 family members in S. cerevisiae. Critically, species-specific silencing of the S. bayanus HMR locus could be reconstituted in S. cerevisiae by co-transfer of the S. bayanus Sir4 and Kos3 (the ancestral relative of Sir1) proteins. As Sir1/Kos3 and Sir4 bind conserved silencer-binding proteins, but not specific DNA sequences, these rapidly evolving proteins served to interpret differences in the two species' silencers presumably involving emergent features created by the regulatory proteins that bind sequences within silencers. The results presented here, and in particular the high resolution ChIP-Seq localization of the Sir4 protein, provided unanticipated insights into the mechanism of silent chromatin assembly in yeast.National Science Foundation (U.S.) (GM31105)National Science Foundation (U.S.) (Predoctoral Fellowships

Engineering Effective Response to Outbreaks of Influenza

Objective. Allocation of vaccines and deployment of non-pharmaceutical interventions (NPIs) are critical to controlling influenza. We examine how these policies can minimize the societal impact. Methods. An engineering systems framing and modeling approach incorporates theories and data on the spread of influenza. Models employed data from the CDC and state governments on cases and vaccine administered during the 2009 H1N1 outbreak, and published literature on how to reduce human-to-human contacts. Results. During the outbreak, barely half of all states received proportional allotments of vaccine in time to protect any citizens, while fewer sought vaccine after the peak. While individuals prone to contract and spread infection drive the progression, diligent hygiene practices and social distancing measures can drive down the number of cases. Conclusions. NPIs are highly effective in reducing the spread of influenza before, but also after vaccine is administered. Policies to allocate vaccine in direct proportion to population should be replaced and larger stocks sent to regions where greater numbers of persons stand to be protected

The Enigmatic Conservation of a Rap1 Binding Site in the Saccharomyces cerevisiae HMR-E Silencer

Silencing at the HMR and HML loci in Saccharomyces cerevisiae requires recruitment of Sir proteins to the HML and HMR silencers. The silencers are regulatory sites flanking both loci and consisting of binding sites for the Rap1, Abf1, and ORC proteins, each of which also functions at hundreds of sites throughout the genome in processes unrelated to silencing. Interestingly, the sequence of the binding site for Rap1 at the silencers is distinct from the genome-wide binding profile of Rap1, being a weaker match to the consensus, and indeed is bound with low affinity relative to the consensus sequence. Remarkably, this low-affinity Rap1 binding site variant was conserved among silencers of the sensu stricto Saccharomyces species, maintained as a poor match to the Rap1 genome-wide consensus sequence in all of them. We tested multiple predictions about the possible role of this binding-site variant in silencing by substituting the native Rap1 binding site at the HMR-E silencer with the genome-wide consensus sequence for Rap1. Contrary to the predictions from the current models of Rap1, we found no influence of the Rap1 binding site version on the kinetics of establishing silencing, nor on the maintenance of silencing, nor the extent of silencing. We further explored implications of these findings with regard to prevention of ectopic silencing, and deduced that the selective pressure for the unprecedented conservation of this binding site variant may not be related to silencing.National Science Foundation (U.S.) (Predoctoral Fellowship)National Institutes of Health (U.S.) (Grant GM31105

Lessons Learned from Positon-Electron Project Low Level RF and Longitudinal Feedback

The PEP-II B-Factory collider ended the final phase of operation at nearly twice the design current and 4X the design luminosity. To highlight the evolution from the original conceptual design through to the 1.2E34 final machine we choose one example each from the broadband feedback and from the LLRF system. They illustrate the original design estimation missed some very significant details, and how in the course of PEP-II operation unexpected difficulties led to significant insights and new approaches which allowed higher machine performance. We present valuable ”lessons learned” which are of interest to designers of next generation feedback and impedance controlled LLRF systems

Recent Observations on a Horizontal Instability in the DAFNE Positron Ring

A strong horizontal instability limits the maximum positron current storable in the DAFNE Phi-Factory. A powerful feedback system makes it possible to store and put in collision more than 1300 mA of positron current in 105-109 bunches. Nevertheless, a much higher current (>2.4A) has been successfully stored in the twin electron ring. Measurements have been carried out to understand the positron current limit and to characterize the behavior of the horizontal instability at high current with different bunch patterns. Grow/damp turn-by-turn data obtained by turning off the horizontal feedback have been acquired and analyzed. Spectral analysis and growth rates of the instability are shown. In particular, the -1 mode has strong evidence and fast growth rate. Its growth rate behavior is analyzed at different beam currents and bunch patterns