Combinatorial Roles of Heparan Sulfate Proteoglycans and Heparan Sulfates in Caenorhabditis elegans Neural Development

Heparan sulfate proteoglycans (HSPGs) play critical roles in the development and adult physiology of all metazoan organisms. Most of the known molecular interactions of HSPGs are attributed to the structurally highly complex heparan sulfate (HS) glycans. However, whether a specific HSPG (such as syndecan) contains HS modifications that differ from another HSPG (such as glypican) has remained largely unresolved. Here, a neural model in C. elegans is used to demonstrate for the first time the relationship between specific HSPGs and HS modifications in a defined biological process in vivo. HSPGs are critical for the migration of hermaphrodite specific neurons (HSNs) as genetic elimination of multiple HSPGs leads to 80% defect of HSN migration. The effects of genetic elimination of HSPGs are additive, suggesting that multiple HSPGs, present in the migrating neuron and in the matrix, act in parallel to support neuron migration. Genetic analyses suggest that syndecan/sdn-1 and HS 6-O-sulfotransferase, hst-6, function in a linear signaling pathway and glypican/lon-2 and HS 2-O-sulfotransferase, hst-2, function together in a pathway that is parallel to sdn-1 and hst-6. These results suggest core protein specific HS modifications that are critical for HSN migration. In C. elegans, the core protein specificity of distinct HS modifications may be in part regulated at the level of tissue specific expression of genes encoding for HSPGs and HS modifying enzymes. Genetic analysis reveals that there is a delicate balance of HS modifications and eliminating one HS modifying enzyme in a compromised genetic background leads to significant changes in the overall phenotype. These findings are of importance with the view of HS as a critical regulator of cell signaling in normal development and disease

Entry in the ADHD drugs market: Welfare impact of generics and me-toos

Recent decades have seen a growth in treatments for attention deficit hyperactivity disorder (ADHD) including many branded and generic drugs. In the early 2000's, new drug entry dramatically altered market shares. We estimate a demand system for ADHD drugs and assess the welfare impact of new drugs. We find that entry induced large welfare gains by reducing prices of substitute drugs, and by providing alternative delivery mechanisms for existing molecules. Our results suggest that the success of follow-on patented drugs may come from unanticipated innovations like delivery mechanisms, a factor ignored by proposals to retard new follow-on drug approvals

Political institutions and debt crises

This paper shows that political institutions matter in explaining defaults on external and domestic debt obligations. We explore a large number of political and macroeconomic variables using a non-parametric technique to predict safety from default. The advantage of this technique is that it is able to identify patterns in the data that are not captured in standard probit analysis. We find that political factors matter, and do so in different ways for democratic and non-democratic regimes, and for domestic and external debt. In democracies, a parliamentary system or sufficient checks and balances almost guarantee the absence of default on external debt when economic fundamentals or liquidity are sufficiently strong. In dictatorships, high stability and tenure play a similar role for default on domestic debt

Use of in vitro human keratinocyte models to study the effect of cooling on chemotherapy drug-induced cytotoxicity

A highly distressing side-effect of cancer chemotherapy is chemotherapy-induced alopecia (CIA). Scalp cooling remains the only treatment for CIA, yet there is no experimental evidence to support the cytoprotective capacity of cooling. We have established a series of in vitro models for the culture of human keratinocytes under conditions where they adopt a basal, highly-proliferative phenotype thus resembling the rapidly-dividing sub-population of native hair-matrix keratinocytes. Using a panel of chemotherapy drugs routinely used clinically (docetaxel, doxorubicin and the active metabolite of cyclophosphamide 4-OH-CP), we demonstrate that although these drugs are highly-cytotoxic, cooling can markedly reduce or completely inhibit drug cytotoxicity, in agreement with clinical observations. By contrast, we show that cytotoxicity caused by specific combinatorial drug treatments cannot be adequately attenuated by cooling, supporting data showing that such treatments do not always respond well to cooling clinically. Importantly, we provide evidence that the choice of temperature may be critical in determining the efficacy of cooling in rescuing cells from drug-mediated toxicity. Therefore, despite their reductive nature, these in vitro models have provided experimental evidence for the clinically-reported cytoprotective role of cooling and represent useful tools for future studies on the molecular mechanisms of cooling-mediated cytoprotection

Early stage morphology of quench condensed Ag, Pb and Pb/Ag hybrid films

Scanning Tunneling Microscopy (STM) has been used to study the morphology of Ag, Pb and Pb/Ag bilayer films fabricated by quench condensation of the elements onto cold (T=77K), inert and atomically flat Highly Oriented Pyrolytic Graphite (HOPG) substrates. All films are thinner than 10 nm and show a granular structure that is consistent with earlier studies of QC films. The average lateral diameter, $\bar {2r}$, of the Ag grains, however, depends on whether the Ag is deposited directly on HOPG ($\bar {2r}$ = 13 nm) or on a Pb film consisting of a single layer of Pb grains ($\bar {2r}$ = 26.8 nm). In addition, the critical thickness for electrical conduction ($d_{G}$) of Pb/Ag films on inert glass substrates is substantially larger than for pure Ag films. These results are evidence that the structure of the underlying substrate exerts an influence on the size of the grains in QC films. We propose a qualitative explanation for this previously unencountered phenomenon.Comment: 11 pages, 3 figures and one tabl

3D time series analysis of cell shape using Laplacian approaches

Background: Fundamental cellular processes such as cell movement, division or food uptake critically depend on cells being able to change shape. Fast acquisition of three-dimensional image time series has now become possible, but we lack efficient tools for analysing shape deformations in order to understand the real three-dimensional nature of shape changes. Results: We present a framework for 3D+time cell shape analysis. The main contribution is three-fold: First, we develop a fast, automatic random walker method for cell segmentation. Second, a novel topology fixing method is proposed to fix segmented binary volumes without spherical topology. Third, we show that algorithms used for each individual step of the analysis pipeline (cell segmentation, topology fixing, spherical parameterization, and shape representation) are closely related to the Laplacian operator. The framework is applied to the shape analysis of neutrophil cells. Conclusions: The method we propose for cell segmentation is faster than the traditional random walker method or the level set method, and performs better on 3D time-series of neutrophil cells, which are comparatively noisy as stacks have to be acquired fast enough to account for cell motion. Our method for topology fixing outperforms the tools provided by SPHARM-MAT and SPHARM-PDM in terms of their successful fixing rates. The different tasks in the presented pipeline for 3D+time shape analysis of cells can be solved using Laplacian approaches, opening the possibility of eventually combining individual steps in order to speed up computations

Lunar Outgassing, Transient Phenomena and The Return to The Moon, I: Existing Data

Herein the transient lunar phenomena (TLP) report database is subjected to a discriminating statistical filter robust against sites of spurious reports, and produces a restricted sample that may be largely reliable. This subset is highly correlated geographically with the catalog of outgassing events seen by the Apollo 15, 16 and Lunar Prospector alpha-particle spectrometers for episodic Rn-222 gas release. Both this robust TLP sample and even the larger, unfiltered sample are highly correlated with the boundary between mare and highlands, as are both deep and shallow moonquakes, as well as Po-210, a long-lived product of Rn-222 decay and a further tracer of outgassing. This offers another significant correlation relating TLPs and outgassing, and may tie some of this activity to sagging mare basalt plains (perhaps mascons). Additionally, low-level but likely significant TLP activity is connected to recent, major impact craters (while moonquakes are not), which may indicate the effects of cracks caused by the impacts, or perhaps avalanches, allowing release of gas. The majority of TLP (and Rn-222) activity, however, is confined to one site that produced much of the basalt in the Procellarum Terrane, and it seems plausible that this TLP activity may be tied to residual outgassing from the formerly largest volcanic ffusion sites from the deep lunar interior. With the coming in the next few years of robotic spacecraft followed by human exploration, the study of TLPs and outgassing is both promising and imperiled. We will have an unprecedented pportunity to study lunar outgassing, but will also deal with a greater burden of anthropogenic lunar gas than ever produced. There is a pressing need to study lunar atmosphere and its sources while still pristine. [Abstract abridged.]Comment: 35 pages, 3 figures, submitted to Icarus. Other papers in series found at http://www.astro.columbia.edu/~arlin/TLP