Hippocampal Infusion of Zeta Inhibitory Peptide Impairs Recent, but Not Remote, Recognition Memory in Rats.

Spatial memory in rodents can be erased following the infusion of zeta inhibitory peptide (ZIP) into the dorsal hippocampus via indwelling guide cannulas. It is believed that ZIP impairs spatial memory by reversing established late-phase long-term potentiation (LTP). However, it is unclear whether other forms of hippocampus-dependent memory, such as recognition memory, are also supported by hippocampal LTP. In the current study, we tested recognition memory in rats following hippocampal ZIP infusion. In order to combat the limited targeting of infusions via cannula, we implemented a stereotaxic approach for infusing ZIP throughout the dorsal, intermediate, and ventral hippocampus. Rats infused with ZIP 3-7 days after training on the novel object recognition task exhibited impaired object recognition memory compared to control rats (those infused with aCSF). In contrast, rats infused with ZIP 1 month after training performed similar to control rats. The ability to form new memories after ZIP infusions remained intact. We suggest that enhanced recognition memory for recent events is supported by hippocampal LTP, which can be reversed by hippocampal ZIP infusion

Modeling the Risk of Fire/Explosion Due to Oxidizer/Fuel Leaks in the Ares I Interstage

A significant flight hazard associated with liquid propellants, such as those used in the upper stage of NASA's new Ares I launch vehicle, is the possibility of leakage of hazardous fluids resulting in a catastrophic fire/explosion. The enclosed and vented interstage of the Ares I contains numerous oxidizer and fuel supply lines as well as ignition sources. The potential for fire/explosion due to leaks during ascent depends on the relative concentrations of hazardous and inert fluids within the interstage along with other variables such as pressure, temperature, leak rates, and fluid outgasing rates. This analysis improves on previous NASA Probabilistic Risk Assessment (PRA) estimates of the probability of deflagration, in which many of the variables pertinent to the problem were not explicitly modeled as a function of time. This paper presents the modeling methodology developed to analyze these risks

Phase field approach to optimal packing problems and related Cheeger clusters

In a fixed domain of $\Bbb{R}^N$ we study the asymptotic behaviour of optimal clusters associated to $\alpha$-Cheeger constants and natural energies like the sum or maximum: we prove that, as the parameter $\alpha$ converges to the "critical" value $\Big (\frac{N-1}{N}\Big ) _+$, optimal Cheeger clusters converge to solutions of different packing problems for balls, depending on the energy under consideration. As well, we propose an efficient phase field approach based on a multiphase Gamma convergence result of Modica-Mortola type, in order to compute $\alpha$-Cheeger constants, optimal clusters and, as a consequence of the asymptotic result, optimal packings. Numerical experiments are carried over in two and three space dimensions

Teratology Primer-2nd Edition (7/9/2010)

Foreword: What is Teratology? “What a piece of work is an embryo!” as Hamlet might have said. “In form and moving how express and admirable! In complexity how infinite!” It starts as a single cell, which by repeated divisions gives rise to many genetically identical cells. These cells receive signals from their surroundings and from one another as to where they are in this ball of cells —front or back, right or left, headwards or tailwards, and what they are destined to become. Each cell commits itself to being one of many types; the cells migrate, combine into tissues, or get out of the way by dying at predetermined times and places. The tissues signal one another to take their own pathways; they bend, twist, and form organs. An organism emerges. This wondrous transformation from single celled simplicity to myriad-celled complexity is programmed by genes that, in the greatest mystery of all, are turned on and off at specified times and places to coordinate the process. It is a wonder that this marvelously emergent operation, where there are so many opportunities for mistakes, ever produces a well-formed and functional organism. And sometimes it doesn’t. Mistakes occur. Defective genes may disturb development in ways that lead to death or to malformations. Extrinsic factors may do the same. “Teratogenic” refers to factors that cause malformations, whether they be genes or environmental agents. The word comes from the Greek “teras,” for “monster,” a term applied in ancient times to babies with severe malformations, which were considered portents or, in the Latin, “monstra.” Malformations can happen in many ways. For example, when the neural plate rolls up to form the neural tube, it may not close completely, resulting in a neural tube defect—anencephaly if the opening is in the head region, or spina bifida if it is lower down. The embryonic processes that form the face may fail to fuse, resulting in a cleft lip. Later, the shelves that will form the palate may fail to move from the vertical to the horizontal, where they should meet in the midline and fuse, resulting in a cleft palate. Or they may meet, but fail to fuse, with the same result. The forebrain may fail to induce the overlying tissue to form the eye, so there is no eye (anophthalmia). The tissues between the toes may fail to break down as they should, and the toes remain webbed. Experimental teratology flourished in the 19th century, and embryologists knew well that the development of bird and frog embryos could be deranged by environmental “insults,” such as lack of oxygen (hypoxia). But the mammalian uterus was thought to be an impregnable barrier that would protect the embryo from such threats. By exclusion, mammalian malformations must be genetic, it was thought. In the early 1940s, several events changed this view. In Australia an astute ophthalmologist, Norman Gregg, established a connection between maternal rubella (German measles) and the triad of cataracts, heart malformations, and deafness. In Cincinnati Josef Warkany, an Austrian pediatrician showed that depriving female rats of vitamin B (riboflavin) could cause malformations in their offspring— one of the early experimental demonstrations of a teratogen. Warkany was trying to produce congenital cretinism by putting the rats on an iodine deficient diet. The diet did indeed cause malformations, but not because of the iodine deficiency; depleting the diet of iodine had also depleted it of riboflavin! Several other teratogens were found in experimental animals, including nitrogen mustard (an anti cancer drug), trypan blue (a dye), and hypoxia (lack of oxygen). The pendulum was swinging back; it seemed that malformations were not genetically, but environmentally caused. In Montreal, in the early 1950s, Clarke Fraser’s group wanted to bring genetics back into the picture. They had found that treating pregnant mice with cortisone caused cleft palate in the offspring, and showed that the frequency was high in some strains and low in others. The only difference was in the genes. So began “teratogenetics,” the study of how genes influence the embryo’s susceptibility to teratogens. The McGill group went on to develop the idea that an embryo’s genetically determined, normal, pattern of development could influence its susceptibility to a teratogen— the multifactorial threshold concept. For instance, an embryo must move its palate shelves from vertical to horizontal before a certain critical point or they will not meet and fuse. A teratogen that causes cleft palate by delaying shelf movement beyond this point is more likely to do so in an embryo whose genes normally move its shelves late. As studies of the basis for abnormal development progressed, patterns began to appear, and the principles of teratology were developed. These stated, in summary, that the probability of a malformation being produced by a teratogen depends on the dose of the agent, the stage at which the embryo is exposed, and the genotype of the embryo and mother. The number of mammalian teratogens grew, and those who worked with them began to meet from time to time, to talk about what they were finding, leading, in 1960, to the formation of the Teratology Society. There were, of course, concerns about whether these experimental teratogens would be a threat to human embryos, but it was thought, by me at least, that they were all “sledgehammer blows,” that would be teratogenic in people only at doses far above those to which human embryos would be exposed. So not to worry, or so we thought. Then came thalidomide, a totally unexpected catastrophe. The discovery that ordinary doses of this supposedly “harmless” sleeping pill and anti-nauseant could cause severe malformations in human babies galvanized this new field of teratology. Scientists who had been quietly working in their laboratories suddenly found themselves spending much of their time in conferences and workshops, sitting on advisory committees, acting as consultants for pharmaceutical companies, regulatory agencies, and lawyers, as well as redesigning their research plans. The field of teratology and developmental toxicology expanded rapidly. The following pages will show how far we have come, and how many important questions still remain to be answered. A lot of effort has gone into developing ways to predict how much of a hazard a particular experimental teratogen would be to the human embryo (chapters 9–19). It was recognized that animal studies might not prove a drug was “safe” for the human embryo (in spite of great pressure from legislators and the public to do so), since species can vary in their responses to teratogenic exposures. A number of human teratogens have been identified, and some, suspected of teratogenicity, have been exonerated—at least of a detectable risk (chapters 21–32). Regulations for testing drugs before market release have greatly improved (chapter 14). Other chapters deal with how much such things as population studies (chapter 11), post-marketing surveillance (chapter 13), and systems biology (chapter 16) add to our understanding. And, in a major advance, the maternal role of folate in preventing neural tube defects and other birth defects is being exploited (chapter 32). Encouraging women to take folic acid supplements and adding folate to flour have produced dramatic falls in the frequency of neural tube defects in many parts of the world. Progress has been made not only in the use of animal studies to predict human risks, but also to illumine how, and under what circumstances, teratogens act to produce malformations (chapters 2–8). These studies have contributed greatly to our knowledge of abnormal and also normal development. Now we are beginning to see exactly when and where the genes turn on and off in the embryo, to appreciate how they guide development and to gain exciting new insights into how genes and teratogens interact. The prospects for progress in the war on birth defects were never brighter. F. Clarke Fraser McGill University (Emeritus) Montreal, Quebec, Canad

Autonomous Seawater \u3ci\u3ep\u3c/i\u3eCO\u3csub\u3e2\u3c/sub\u3e and pH Time Series From 40 Surface Buoys and the Emergence of Anthropogenic Trends

Ship-based time series, some now approaching over 3 decades long, are critical climate records that have dramatically improved our ability to characterize natural and anthropogenic drivers of ocean carbon dioxide (CO2) uptake and biogeochemical processes. Advancements in autonomous marine carbon sensors and technologies over the last 2 decades have led to the expansion of observations at fixed time series sites, thereby improving the capability of characterizing sub-seasonal variability in the ocean. Here , we present a data product of 40 individual autonomous moored surface ocean pCO2 (partial pressure of CO2) time series established between 2004 and 2013, 17 also include autonomous pH measurements. These time series characterie a wide range of surface ocean carbonate conditions in diffferent oceanic (17 sites), coastal (13 sites), and coral reef (10 sites) regimes. A time of trend emergence (ToE) methodology applied ot the time series that exhibit well-constrained daily to interannual variability and an estimate of decadal variability indicates that the length of sustained observations necessary to detect statistically significant anthropogenic trends varies by marine environment. The ToE estisites, and 9 to 22 years at the coral reef sites. Only two open ocean pCO2 and pH range from 8 to 15 years at the open ocean sites, 16 to 41 years at the coastal sites, and 9 to 22 years at the coral reef sites. Only two open ocean pCO2 time series, Woods Hole Oceanographic Institution Hawaii Ocean Time-series Station (WHOTS) in the subtropical North Pacific and Stratus n the South Pacific gyre, have been deployed longer than the estimated trend detection time and, for these, deseasoned monthly means show estimated anthropogenic trends of 1.9 ± 0.3 and 1.6 ± 0.3 μatm yr-1, respectively. In the future, it is possible that updates to this product will allow for the estimation of anthropogenic trends at more sites; however, the product currently provides a valuable tool in an accessible format for evaluating climatology and natural variability of surface ocean carbonate chemistry in a variety of regions. Data are available at https://doi.org/10.7289/V5DB8043 and https://www.nodc.noaa.gov/ocads/oceans/Moorings/ndp097.html (Sutton et al., 2018)

The Early Nutritional Environment of Mice Determines the Capacity for Adipose Tissue Expansion by Modulating Genes of Caveolae Structure

While the phenomenon linking the early nutritional environment to disease susceptibility exists in many mammalian species, the underlying mechanisms are unknown. We hypothesized that nutritional programming is a variable quantitative state of gene expression, fixed by the state of energy balance in the neonate, that waxes and wanes in the adult animal in response to changes in energy balance. We tested this hypothesis with an experiment, based upon global gene expression, to identify networks of genes in which expression patterns in inguinal fat of mice have been altered by the nutritional environment during early post-natal development. The effects of over- and under-nutrition on adiposity and gene expression phenotypes were assessed at 5, 10, 21 days of age and in adult C57Bl/6J mice fed chow followed by high fat diet for 8 weeks. Under-nutrition severely suppressed plasma insulin and leptin during lactation and diet-induced obesity in adult mice, whereas over-nourished mice were phenotypically indistinguishable from those on a control diet. Food intake was not affected by under- or over-nutrition. Microarray gene expression data revealed a major class of genes encoding proteins of the caveolae and cytoskeleton, including Cav1, Cav2, Ptrf (Cavin1), Ldlr, Vldlr and Mest, that were highly associated with adipose tissue expansion in 10 day-old mice during the dynamic phase of inguinal fat development and in adult animals exposed to an obesogenic environment. In conclusion gene expression profiles, fat mass and adipocyte size in 10 day old mice predicted similar phenotypes in adult mice with variable diet-induced obesity. These results are supported by phenotypes of KO mice and suggest that when an animal enters a state of positive energy balance adipose tissue expansion is initiated by coordinate changes in mRNA levels for proteins required for modulating the structure of the caveolae to maximize the capacity of the adipocyte for lipid storage

Guidelines for Modeling and Reporting Health Effects of Climate Change Mitigation Actions.

BACKGROUND: Modeling suggests that climate change mitigation actions can have substantial human health benefits that accrue quickly and locally. Documenting the benefits can help drive more ambitious and health-protective climate change mitigation actions; however, documenting the adverse health effects can help to avoid them. Estimating the health effects of mitigation (HEM) actions can help policy makers prioritize investments based not only on mitigation potential but also on expected health benefits. To date, however, the wide range of incompatible approaches taken to developing and reporting HEM estimates has limited their comparability and usefulness to policymakers. OBJECTIVE: The objective of this effort was to generate guidance for modeling studies on scoping, estimating, and reporting population health effects from climate change mitigation actions. METHODS: An expert panel of HEM researchers was recruited to participate in developing guidance for conducting HEM studies. The primary literature and a synthesis of HEM studies were provided to the panel. Panel members then participated in a modified Delphi exercise to identify areas of consensus regarding HEM estimation. Finally, the panel met to review and discuss consensus findings, resolve remaining differences, and generate guidance regarding conducting HEM studies. RESULTS: The panel generated a checklist of recommendations regarding stakeholder engagement: HEM modeling, including model structure, scope and scale, demographics, time horizons, counterfactuals, health response functions, and metrics; parameterization and reporting; approaches to uncertainty and sensitivity analysis; accounting for policy uptake; and discounting. DISCUSSION: This checklist provides guidance for conducting and reporting HEM estimates to make them more comparable and useful for policymakers. Harmonization of HEM estimates has the potential to lead to advances in and improved synthesis of policy-relevant research that can inform evidence-based decision making and practice. https://doi.org/10.1289/EHP6745