Wavelength Accuracy of the Keck HIRES Spectrograph and Measuring Changes in the Fine Structure Constant

We report on an attempt to accurately wavelength calibrate four nights of data taken with the Keck HIRES spectrograph on QSO PHL957, for the purpose of determining whether the fine structure constant was different in the past. Using new software and techniques, we measured the redshifts of various Ni II, Fe II, Si II, etc. lines in a damped Ly-alpha system at z=2.309. Roughly half the data was taken through the Keck iodine cell which contains thousands of well calibrated iodine lines. Using these iodine exposures to calibrate the normal Th-Ar Keck data pipeline output we found absolute wavelength offsets of 500 m/s to 1000 m/s with drifts of more than 500 m/s over a single night, and drifts of nearly 2000 m/s over several nights. These offsets correspond to an absolute redshift of uncertainty of about Delta z=10^{-5} (Delta lambda= 0.02 Ang), with daily drifts of around Delta z=5x10^{-6} (Delta lambda =0.01 Ang), and multiday drifts of nearly Delta z=2x10^{-5} (0.04 Ang). The causes of the wavelength offsets are not known, but since claimed shifts in the fine structure constant would result in velocity shifts of less than 100 m/s, this level of systematic uncertainty makes may make it difficult to use Keck HIRES data to constrain the change in the fine structure constant. Using our calibrated data, we applied both our own fitting software and standard fitting software to measure (Delta alpha)/alpha, but discovered that we could obtain results ranging from significant detection of either sign, to strong null limits, depending upon which sets of lines and which fitting method was used. We thus speculate that the discrepant results on (Delta alpha)/alpha reported in the literature may be due to random fluctuations coming from under-estimated systematic errors in wavelength calibration and fitting procedure.Comment: 19 pages, 10 figures, to appear in ApJ, Dec 2009 Many corrections and changes made, some new figure

Kinetic Characterization of Salmonella FliK-FlhB Interactions Demonstrates Complexity of the Type III Secretion Substrate-Specificity Switch

The bacterial flagellum is a complex macromolecular machine consisting of more than 20000 proteins, most of which must be exported from the cell via a dedicated Type III secretion apparatus. At a defined point in flagellar morphogenesis, hook completion is sensed and the apparatus switches substrate specificity type from rod and hook proteins to filament ones. How the switch works is a subject of intense interest. FIiK and F1hBs play central roles. In the present study, two optical biosensing methods were used to characterize FIiK-F1hB interactions using wild-type and two variant FlhBs from mutants with severe flagellar structural defects. Binding was found to be complex with fast and slow association and dissociation components. Surprisingly, wild-type and variant FlhBs had similar kinetic profiles and apparent affinities, which ranged between I and 10.5 μM, suggesting that the specificity switch is more complex than presently understood. Other binding experiments provided evidence for a conformational change after binding. Liquid chromatography-mass spectrometry (LC-MS) and NMR experiments were performed to identify a cyclic intermediate product whose existence supports the mechanism of autocatalytic cleavage at FlhB residue N269. The present results show that while autocatalytic cleavage is necessary for proper substrate specificity switching, it does not result in an altered interaction with FIiK. strongly suggesting the involvement of other proteins in the mechanism

Taking the long view on writing development

Studies on writing development have grown in diversity and depth in recent decades, but remain fragmented along lines of theory, method, and age ranges or populations studied. Meaningful, competent writing performances that meet the demands of the moment rely on many kinds of well-practiced and deeply understood capacities working together; however, these capacities’ realization and developmental trajectories can vary from one individual to another. Without an integrated framework to understand lifespan development of writing abilities in its variation, high-stakes decisions about curriculum, instruction, and assessment are often made in unsystematic ways that may fail to support the development they are intended to facilitate; further, research may not consider the range of issues at stake in studying writing in any particular moment. To address this need and synthesize what is known about the various dimensions of writing development at different ages, the coauthors of this essay have engaged in sustained discussion, drawing on a range of theoretical and methodological perspectives. Drawing on research from different disciplinary perspectives, they propose eight principles upon which an account of writing development consistent with research findings could be founded. These principles are proposed as a basis for further lines of inquiry into how writing develops across the lifespan

Scaffold Translation: Barriers Between Concept and Clinic

Translation of scaffold-based bone tissue engineering (BTE) therapies to clinical use remains, bluntly, a failure. This dearth of translated tissue engineering therapies (including scaffolds) remains despite 25 years of research, research funding totaling hundreds of millions of dollars, over 12,000 papers on BTE and over 2000 papers on BTE scaffolds alone in the past 10 years (PubMed search). Enabling scaffold translation requires first an understanding of the challenges, and second, addressing the complete range of these challenges. There are the obvious technical challenges of designing, manufacturing, and functionalizing scaffolds to fill the Form, Fixation, Function, and Formation needs of bone defect repair. However, these technical solutions should be targeted to specific clinical indications (e.g., mandibular defects, spine fusion, long bone defects, etc.). Further, technical solutions should also address business challenges, including the need to obtain regulatory approval, meet specific market needs, and obtain private investment to develop products, again for specific clinical indications. Finally, these business and technical challenges present a much different model than the typical research paradigm, presenting the field with philosophical challenges in terms of publishing and funding priorities that should be addressed as well. In this article, we review in detail the technical, business, and philosophical barriers of translating scaffolds from Concept to Clinic. We argue that envisioning and engineering scaffolds as modular systems with a sliding scale of complexity offers the best path to addressing these translational challenges.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90495/1/ten-2Eteb-2E2011-2E0251.pd

Financing Direct Democracy: Revisiting the Research on Campaign Spending and Citizen Initiatives

The conventional view in the direct democracy literature is that spending against a measure is more effective than spending in favor of a measure, but the empirical results underlying this conclusion have been questioned by recent research. We argue that the conventional finding is driven by the endogenous nature of campaign spending: initiative proponents spend more when their ballot measure is likely to fail. We address this endogeneity by using an instrumental variables approach to analyze a comprehensive dataset of ballot propositions in California from 1976 to 2004. We find that both support and opposition spending on citizen initiatives have strong, statistically significant, and countervailing effects. We confirm this finding by looking at time series data from early polling on a subset of these measures. Both analyses show that spending in favor of citizen initiatives substantially increases their chances of passage, just as opposition spending decreases this likelihood

Macrophage metabolic reprogramming presents a therapeutic target in lupus nephritis.

IgG antibodies cause inflammation and organ damage in autoimmune diseases such as systemic lupus erythematosus (SLE). We investigated the metabolic profile of macrophages isolated from inflamed tissues in immune complex (IC)-associated diseases, including SLE and rheumatoid arthritis, and following IgG Fcγ receptor cross-linking. We found that human and mouse macrophages undergo a switch to glycolysis in response to IgG IC stimulation, mirroring macrophage metabolic changes in inflamed tissue in vivo. This metabolic reprogramming was required to generate a number of proinflammatory mediators, including IL-1β, and was dependent on mTOR and hypoxia-inducible factor (HIF)1α. Inhibition of glycolysis, or genetic depletion of HIF1α, attenuated IgG IC-induced activation of macrophages in vitro, including primary human kidney macrophages. In vivo, glycolysis inhibition led to a reduction in kidney macrophage IL-1β and reduced neutrophil recruitment in a murine model of antibody-mediated nephritis. Together, our data reveal the molecular mechanisms underpinning FcγR-mediated metabolic reprogramming in macrophages and suggest a therapeutic strategy for autoantibody-induced inflammation, including lupus nephritis