SrGAP2-Dependent Integration of Membrane Geometry and Slit-Robo-Repulsive Cues Regulates Fibroblast Contact Inhibition of Locomotion

Migrating fibroblasts undergo contact inhibition of locomotion (CIL), a process that was discovered five decades ago and still is not fully understood at the molecular level. We identify the Slit2-Robo4-srGAP2 signaling network as a key regulator of CIL in fibroblasts. CIL involves highly dynamic contact protrusions with a specialized actin cytoskeleton that stochastically explore cell-cell overlaps between colliding fibroblasts. A membrane curvature-sensing F-BAR domain pre-localizes srGAP2 to protruding edges and terminates their extension phase in response to cell collision. A FRET-based biosensor reveals that Rac1 activity is focused in a band at the tip of contact protrusions, in contrast to the broad activation gradient in contact-free protrusions. SrGAP2 specifically controls the duration of Rac1 activity in contact protrusions, but not in contact-free protrusions. We propose that srGAP2 integrates cell edge curvature and Slit-Robo-mediated repulsive cues to fine-tune Rac1 activation dynamics in contact protrusions to spatiotemporally coordinate CIL.

Effects of Strand Geometry on Selected Properties of Long-Stand Structural Composite Lumber Made from Northeastern Hardwoods

Structural composite lumber (SCL) products often possess significantly higher design values than the top grades of solid lumber, making it a popular choice for both residential and commercial applications. The enhanced mechanical properties of SCL are mainly due to defect randomization and densification of the wood fiber, both largely functions of the size, shape and composition (species) of the wood element. Traditionally, SCL manufacturers have used thin, rectangular elements produced from either moderate density softwoods or low density hardwoods. Higher density hardwood species have been avoided, as they require higher pressures to adequately densify and consolidate the wood furnish. These higher pressures can lead to increased manufacturing costs, damage to the wood fiber and/or a product that is too dense, making it heavy and unreceptive to common mechanical fastening techniques. In the northeastern United States high density, diffuse-porous hardwoods (such as maple, beech and birch) are abundant. Use of these species as primary furnish for a SCL product may allow for a competitive advantage in terms of resource cost against products that rely on veneer grade logs. Proximity to this abundant and relatively inexpensive resource may facilitate entry of SCL production facilities in the northeastern United States, where currently none exist. However, modifications to current strand sizes, geometries or production techniques will likely be required to allow for use of these species. A new SCL product concept has been invented allowing for use of these high density hardwoods. The product, referred to as long-strand structural composite lumber (LSSCL), uses strands of significantly larger cross sectional areas and volumes than existing SCL products. In spite of the large strand size, satisfactory consolidation is achieved without excessive densification of the wood fiber through use of a symmetrical strand geometric cross-section. LSSCL density is similar to that of existing SCL products, but is due mainly to the inherent density of the species, rather than through densification. An experiment was designed and conducted producing LSSCL from both large (7/16”) and small (1/4”) strands, of both square and triangular geometric cross sections. Testing results indicate that the large, triangular strands produce LSSCL beams with projected design values of: Modulus of elasticity (MOEapp) – 1,750,000 psi; Allowable bending stress (Fb) – 2750 psi; Allowable shear stress (Fv) – 260 psi. Several modifications are recommended which may lead to improvement of these values, likely allowing for competition against existing SCL products.

GMM Based Inference with Standard Stratified Samples when the Aggregate Shares are Known

We show how to do efficient moment based inference using the generalized method of moments (GMM) when data is collected by standard stratified sampling and the maintained assumption is that the aggregate shares are known.

The Congressional Budget Process and the Aggregate Level of Spending

This paper analyzes whether the Congressional budget process (instituted in 1974) leads to lower aggregate spending than does the piece-meal appropriations process that preceded it. Previous theoretical analysis, using spatial models of legislator preferences, is inconclusive. This paper uses a model of interest group lobbying, where a legislature determines spending on a national public good and on subsidies to subsets of the population that belong to nationwide sector-specific interest groups. In the appropriations process, the Appropriations Committee proposes a budget, maximizing the joint welfare of voters and the interest groups, that leads to overspending on subsidies. In the budget process, a Budget Committee proposes an aggregate level of spending (the budget resolution); the Appropriations Committee then proposes a budget. If the lobby groups are not subject to a binding resource constraint, the two institutional structures lead to identical outcomes. With such a constraint, however, there is a free rider problem among the groups in lobbying the Budget Committee, as each group only obtains a small fraction of the benefits from increasing the aggregate budget. If the number of groups is sufficiently large, each takes the budget resolution as given, and lobbies only the Appropriations Committee. The main results are that aggregate spending is lower, and social welfare higher, under the budget process; however, provision of the public good is suboptimal. The paper also presents two extensions: the first endogenizes the enforcement of the budget resolution by incorporating the relevant procedural rules into the model. The second analyzes statutory budget rules that limit spending levels, but can be revised by a simple majority vote. In each case,the free rider problem prevents the groups from securing the required changes to procedural and budget rules.

The Aggregate Demand for Private Health Insurance Coverage in the U.S.

This paper estimates the aggregate demand for private health insurance coverage in the U.S. using an error-correction model and by recognizing that people are without private health insurance for voluntary, structural, frictional, and cyclical reasons and because of public alternatives. Insurance coverage is measured both by the percentage of the population enrolled in private health insurance plans and the completeness of the insurance coverage. Annual data for the period 1966-1999 are used and both short and long run price and income elasticities of demand are estimated. The empirical findings indicate that both private insurance enrollment and completeness are relatively inelastic with respect to changes in price and income in the short and long run. Moreover, private health insurance enrollment is found to be inversely related to the poverty rate, particularly in the short-run. Finally, our results suggest that an increase in the number cyclically uninsured generates less of a welfare loss than an increase in the structurally uninsured.

Inflation Targeting and Output Growth: Evidence from Aggregate European Data

This paper evaluates inflation targeting and assesses its merits by comparing alternative targets in a macroeconomic model. We use European aggregate data to evaluate the performance of alternative policy rules under alternative inflation targets in terms of output losses. We employ two major alternative policy rules, forward-looking and spontaneous adjustment, and three alternative inflation targets, zero percent, two percent, and four percent inflation rates. The simulation findings suggest that forward-looking rules contributed to macroeconomic stability and increase monetary policy credibility. The superiority of a positive inflation target, in terms of output losses, emerges for the aggregate data. The same methodology, when applied to individual countries, however, suggests that country-specific flexible inflation targeting can improve employment prospects in Europe.

STUDYING AGGREGATE FORMATION BY AMYOTROPHIC LATERAL SCLEROSIS-ASSOCIATED MUTANT SOD1 PROTEIN IN DROSOPHILA MODEL

A common pathological hallmark of most neurodegenerative disorders is the presence of protein aggregates in the brain. Understanding the regulation of aggregate formation is thus important for elucidating disease pathogenic mechanisms and finding effective preventive avenues and cures. Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a selective neurodegenerative disorder predominantly affecting motor neurons. The majority of ALS cases are sporadic, however, mutations in superoxide dismutase 1 (SOD1) are responsible for about 20% of familial ALS (fALS). Mutated SOD1 proteins are prone to misfold and form protein aggregates, thus representing a good candidate for studying aggregate formation. The long-term goal of this project is to identify regulators of aggregate formation by mutant SOD1 and other ALS-associated disease proteins. The specific aim of this thesis project is to assess the possibility of using the well-established Drosophila model system to study aggregation by human SOD1 (hSOD1) mutants. To this end, using wild type and the three mutant hSOD1 (A4V, G85R and G93A) most commonly found among fALS, I have generated 16 different SOD1 constructs containing either eGFP or mCherry in-frame fluorescent reporters, established and tested both cell- and animal-based Drosophila hSOD1 models. The experimental strategy allows for clear visualization of ectopic hSOD1 expression as well as versatile co-expression schemes to fully investigate protein aggregation specifically by mutant hSOD1. I have performed pilot cell-transfection experiments and verified induced expression of hSOD1 proteins. Using several tissue- or cell type-specific Gal4 lines, I have confirmed the proper expression of hSOD1 from established transgenic fly lines. Interestingly, in both Drosophila S2 cells and different fly tissues including the eye and motor neurons, robust aggregate formation by either wild type or mutant hSOD1 proteins was not observed. These preliminary observations suggest that Drosophila might not be a good experimental organism to study aggregation and toxicity of mutant hSOD1 protein. Nevertheless this preliminary conclusion implies the potential existence of a potent protective mechanism against mutant hSOD1 aggregation and toxicity in Drosophila. Thus, results from my SOD1-ALS project in Drosophila will help future studies on how to best employ this classic model organism to study ALS and other human brain degenerative diseases.

Present-day King George Island ice cap geometry measured by ground penetrating radar in 2008/09

We present a consistent data set for the ice thickness, the bedrock topography and the ice surface topography of the King George Island ice cap (Arctowski Icefield and the adjacent central part). The data set is composed of groundbased and airborne Ground Penetrating Radar (GPR) and differential GPS (DGPS) measurements, obtained during several field campaigns. The data set incorporates groundbased measurements in the safely accessible inner parts and airborne measurements in the heavily crevassed coastal areas of the ice cap. In particular, the inclusion of airborne GPR measurements with the 30MHz BGR-P30-System developed at the Institute of Geophysics (University of Münster) completes the picture of the ice geometry substantially. The compiled digital elevation model of the bedrock shows a rough, highly variable topography with pronounced valleys, ridges, and troughs. The mean ice thickness is approx. 238m, with a maximum value of approx. 400m in the surveyed area. Noticeable are bounded areas in the bedrock topography below sea level where marine based ice exists.