Supramolecular Assembly of Aminoethylene‐Lipopeptide PMO Conjugates into RNA Splice‐Switching Nanomicelles

Phosphorodiamidate morpholino oligomers (PMOs) are oligonucleotide analogs that can be used for therapeutic modulation of pre‐mRNA splicing. Similar to other classes of nucleic acid‐based therapeutics, PMOs require delivery systems for efficient transport to the intracellular target sites. Here, artificial peptides based on the oligo(ethylenamino) acid succinyl‐tetraethylenpentamine (Stp), hydrophobic modifications, and an azide group are presented, which are used for strain‐promoted azide‐alkyne cycloaddition conjugation with splice‐switching PMOs. By systematically varying the lead structure and formulation, it is determined that the type of contained fatty acid and supramolecular assembly have a critical impact on the delivery efficacy. A compound containing linolenic acid with three cis double bonds exhibits the highest splice‐switching activity and significantly increases functional protein expression in pLuc/705 reporter cells in vitro and after local administration in vivo. Structural and mechanistic studies reveal that the lipopeptide PMO conjugates form nanoparticles, which accelerate cellular uptake and that the content of unsaturated fatty acids enhances endosomal escape. In an in vitro Duchenne muscular dystrophy exon skipping model using H2K‐mdx52 dystrophic skeletal myotubes, the highly potent PMO conjugates mediate significant splice‐switching at very low nanomolar concentrations. The presented aminoethylene‐lipopeptides are thus a promising platform for the generation of PMO‐therapeutics with a favorable activity/toxicity profile.     

Using bald eagles to indicate the health of the Great Lakes' environment

The bald eagle (Haliaeetus leucocephalus) is one of the most studied birds of North America, and a great amount of natural life‐history information, including the response of various stressors on the eagles' ability to reproduce, are well known. In Michigan, the eagle has been chosen to track the trends of bioaccumulative compounds of concern across watersheds in the state. The state has been divided into major watersheds, and 20% of these are surveyed each year. A control area in northern Minnesota, Voyageurs National Park, is also sampled annually. We report here on the methods used, the preliminary results of the 1999 field season, and how differences in mercury concentrations varied over a 10‐year period. Mercury in feathers of nestling eagles declined over time only in Lakes Michigan and Huron, but have not decreased among other subpopulations in Michigan. Concentrations of polychlorinated biphenyls (PCBs) and 4,4′‐DDE in blood plasma from nestling eagles have declined over time for most subpopulations; however, they remain greater for breeding areas associated with the Great Lakes' food web. Sea eagles of the genus Haliaeetus are a good sentinel species to track trends in bioaccumulative compounds in aquatic systems.     

Acoustic Properties of Amorphous Solids at Very Low Temperatures: The Quest for Interacting Tunneling States

We discuss the strain dependence of the acoustic properties of amorphous metals in both normal and superconducting states, in the temperature range 0.1 mK<T<1 K. A crossover is found when the strain energy is of the order of the effective interaction energy between tunneling systems at the corresponding temperature. Our results provide clear evidence for the interaction between tunneling systems, whose energy is in quantitative agreement with theoretical expectations, and reveal that without the knowledge of the corresponding strain dependences, the measured temperature dependences below ～50 mK of the acoustic properties of disordered solids are rather meaningless.     

Determination of the uranium enrichment with the NaIGEM code

The traditional method used to non-destructively determine the uranium enrichment with an NaI detector is based on the “enrichment meter principle” (Progress report LA-4605-MS, Los Alamos National Laboratory, NNM, 1970, p. 19), which involves measuring the intensity of the 186 keV line of ²³⁵U by selecting two regions of interest for the peak and the background. This type of method suffers from several limitations, the most limiting of which are the impossibility to make wall thickness correction or to take the inference of foreign radioisotopes into account. The NaIGEM software (A guide for using NaIGEM code, version 1.5 for DOS and Windows, 2001; Nucl. Instr. and Meth. A 458 (2001) 196) was developed to overcome these limitations by calculating the 186 keV line intensity with a fitting procedure. The code was tested in different measurement conditions on the wide variety of certified samples, in particular, on reprocessed uranium and on depleted material with thick steel filters interposed between the source and the detector. The results are presented to illustrate the performance and limitations of the tested version (A guide for using NaIGEM code, version 1.5 for DOS and Windows, 2001). The general performance is good except in the case of low-enriched uranium in thick containers.     

The Kitty Genovese murder and the social psychology of helping: The parable of the 38 witnesses.

This article argues that an iconic event in the history of helping research--the story of the 38 witnesses who remained inactive during the murder of Kitty Genovese--is not supported by the available evidence. Using archive material, the authors show that there is no evidence for the presence of 38 witnesses, or that witnesses observed the murder, or that witnesses remained inactive. Drawing a distinction between the robust bystander research tradition and the story of the 38 witnesses, the authors explore the consequences of the story for the discipline of psychology. They argue that the story itself plays a key role in psychology textbooks. They also suggest that the story marks a new way of conceptualizing the dangers of immersion in social groups. Finally, they suggest that the story itself has become a modern parable, the telling of which has served to limit the scope of inquiry into emergency helping. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Planning prompts and indexed terms in textbook search tasks.

Text search is a type of strategic reading that involves locating specific goal-relevant information. Previous research has indicated that college and high school students often exhibit inefficient or unsuccessful text-search performance. Consequently, the effects of 2 manipulations on text-search performance were investigated: (1) the presence of indexed terms in a text-search task and (2) the use of a planning prompt before beginning a task. 34 college students engaged in 6 text-search tasks. Half of these tasks contained terms that could be used in an index; half required that a search term be generated. Half of the subjects were randomly assigned to a prompt condition in which they were prompted to plan their search before beginning each task. The results indicated that a planning prompt raised the success level of search performance, as did the presence of terms that were searchable in the textbook's index. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The Air is Always Cleaner on the Other Side: Race,Space, and Ambient Air Toxics Exposures in California

Abstract: Environmental justice advocates have recently focused attention on cumulative exposure in minority neighborhoods due to multiple sources of pollution. This article uses U.S. EPA's National Air Toxics Assessment (NATA) for 1996 to examine environmental inequality in California, a state that has been a recent innovator in environmental justice policy. We first estimate potential lifetime cancer risks from mobile and stationary sources. We then consider the distribution of these risks using both simple comparisons and a multivariate model in which we control for income, land use, and other explanatory factors, as well as spatial correlation. We find large racial disparities in California's “riskscape” as well as inequalities by other factors and suggest several implications for environmental and land use policy.