Methamphetamine enhances caveolar transport of therapeutic agents across the rodent blood-brain barrier

Summary The blood-brain barrier (BBB) restricts clinically relevant accumulation of many therapeutics in the CNS. Low-dose methamphetamine (METH) induces fluid-phase transcytosis across BBB endothelial cells in vitro and could be used to enhance CNS drug delivery. Here, we show that low-dose METH induces significant BBB leakage in rodents ex vivo and in vivo. Notably, METH leaves tight junctions intact and induces transient leakage via caveolar transport, which is suppressed at 4°C and in caveolin-1 (CAV1) knockout mice. METH enhances brain penetration of both small therapeutic molecules, such as doxorubicin (DOX), and large proteins. Lastly, METH improves the therapeutic efficacy of DOX in a mouse model of glioblastoma, as measured by a 25% increase in median survival time and a significant reduction in satellite lesions. Collectively, our data indicate that caveolar transport at the adult BBB is agonist inducible and that METH can enhance drug delivery to the CNS

Multinational tagging efforts illustrate regional scale of distribution and threats for east pacific green turtles (Chelonia mydas agassizii).

Published onlineJournal ArticleResearch Support, Non-U.S. Gov'tThis is the final version of the article. Available from Public Library of Science via the DOI in this record.To further describe movement patterns and distribution of East Pacific green turtles (Chelonia mydas agassizii) and to determine threat levels for this species within the Eastern Pacific. In order to do this we combined published data from existing flipper tagging and early satellite tracking studies with data from an additional 12 satellite tracked green turtles (1996-2006). Three of these were tracked from their foraging grounds in the Gulf of California along the east coast of the Baja California peninsula to their breeding grounds in Michoacán (1337-2928 km). In addition, three post-nesting females were satellite tracked from Colola beach, Michoacán to their foraging grounds in southern Mexico and Central America (941.3-3020 km). A further six turtles were tracked in the Gulf of California within their foraging grounds giving insights into the scale of ranging behaviour. Turtles undertaking long-distance migrations showed a tendency to follow the coastline. Turtles tracked within foraging grounds showed that foraging individuals typically ranged up to 691.6 km (maximum) from release site location. Additionally, we carried out threat analysis (using the cumulative global human impact in the Eastern Pacific) clustering pre-existing satellite tracking studies from Galapagos, Costa Rica, and data obtained from this study; this indicated that turtles foraging and nesting in Central American waters are subject to the highest anthropogenic impact. Considering that turtles from all three rookeries were found to migrate towards Central America, it is highly important to implement conservation plans in Central American coastal areas to ensure the survival of the remaining green turtles in the Eastern Pacific. Finally, by combining satellite tracking data from this and previous studies, and data of tag returns we created the best available distributional patterns for this particular sea turtle species, which emphasized that conservation measures in key areas may have positive consequences on a regional scale.The work was supported by Earthwatch Institute, David and Lucile Packard Foundation, Wallace Research Foundation, PADI Foundation and the Arizona-Sonora Desert Museum. C. E. H. received a Masters degree bursary from the University of Exeter and the European Social Fund and would like to thank Consejo Nacional de Ciencia y Tecnología (Mexico) for support through a PhD scholarship. W. J. N. was supported by a Fulbright Fellowship and a Marshall Fellowship during the period field research in Baja California was conducted. B. J. G. is supported by the Darwin Initiative, European Social Fund and The Natural Environment Research Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Violent video games and morality: a meta-ethical approach

This paper considers what it is about violent video games that leads one reasonably minded person to declare "That is immoral" while another denies it. Three interpretations of video game content a re discussed: reductionist, narrow, and broad. It is argued that a broad interpretation is required for a moral objection to be justified. It is further argued that understanding the meaning of moral utterances – like "x is immoral" – is important to an understanding of why there is a lack of moral consensus when it comes to the content of violent video games. Constructive ecumenical expressivism is presented as a means of explaining what it is that we are doing when we make moral pronouncements and why, when it comes to video game content, differing moral attitudes abound. Constructive ecumenical expressivism is also presented as a means of illuminating what would be required for moral consensus to be achieved

High-throughput, quantitative analyses of genetic interactions in E. coli.

Large-scale genetic interaction studies provide the basis for defining gene function and pathway architecture. Recent advances in the ability to generate double mutants en masse in Saccharomyces cerevisiae have dramatically accelerated the acquisition of genetic interaction information and the biological inferences that follow. Here we describe a method based on F factor-driven conjugation, which allows for high-throughput generation of double mutants in Escherichia coli. This method, termed genetic interaction analysis technology for E. coli (GIANT-coli), permits us to systematically generate and array double-mutant cells on solid media in high-density arrays. We show that colony size provides a robust and quantitative output of cellular fitness and that GIANT-coli can recapitulate known synthetic interactions and identify previously unidentified negative (synthetic sickness or lethality) and positive (suppressive or epistatic) relationships. Finally, we describe a complementary strategy for genome-wide suppressor-mutant identification. Together, these methods permit rapid, large-scale genetic interaction studies in E. coli

Semianalytical Universal Simulation of the Electrical Properties of the Permeable Base Transistor

Using only a few numerical calculations, we give the analytical current-voltage and charge-voltage characteristics valid for any PBT. The highest unity current gain frequency (f,) corresponding to the current technology is on the order of 30 GHz; nevertheless, the oscillation frequency can be higher than 100 GHz. 1

Resolving issues with environmental impact assessment of marine renewable energy installations

ArticleThis Document is Protected by copyright and was first published by Frontiers. All rights reserved. it is reproduced with permission.Growing concerns about climate change and energy security have fueled a rapid increase in the development of marine renewable energy installations (MREIs). The potential ecological consequences of increased use of these devices emphasizes the need for high quality environmental impact assessment (EIA). We demonstrate that these processes are hampered severely, primarily because ambiguities in the legislation and lack of clear implementation guidance are such that they do not ensure robust assessment of the significance of impacts and cumulative effects. We highlight why the regulatory framework leads to conceptual ambiguities and propose changes which, for the most part, do not require major adjustments to standard practice. We emphasize the importance of determining the degree of confidence in impacts to permit the likelihood as well as magnitude of impacts to be quantified and propose ways in which assessment of population-level impacts could be incorporated into the EIA process. Overall, however, we argue that, instead of trying to ascertain which particular developments are responsible for tipping an already heavily degraded marine environment into an undesirable state, emphasis should be placed on better strategic assessment.Technology Strategy Boar

The Sec1/Munc18 protein Vps45 regulates cellular levels of its SNARE binding partners Tlg2 and Snc2 in Saccharomyces cerevisiae

Intracellular membrane trafficking pathways must be tightly regulated to ensure proper functioning of all eukaryotic cells. Central to membrane trafficking is the formation of specific SNARE (soluble N-ethylmeleimide-sensitive factor attachment protein receptor) complexes between proteins on opposing lipid bilayers. The Sec1/Munc18 (SM) family of proteins play an essential role in SNARE-mediated membrane fusion, and like the SNAREs are conserved through evolution from yeast to humans. The SM protein Vps45 is required for the formation of yeast endosomal SNARE complexes and is thus essential for traffic through the endosomal system. Here we report that, in addition to its role in regulating SNARE complex assembly, Vps45 regulates cellular levels of its SNARE binding partners: the syntaxin Tlg2 and the v-SNARE Snc2: Cells lacking Vps45 have reduced cellular levels of Tlg2 and Snc2; and elevation of Vps45 levels results in concomitant increases in the levels of both Tlg2 and Snc2. As well as regulating traffic through the endosomal system, the Snc v-SNAREs are also required for exocytosis. Unlike most vps mutants, cells lacking Vps45 display multiple growth phenotypes. Here we report that these can be reversed by selectively restoring Snc2 levels in vps45 mutant cells. Our data indicate that as well as functioning as part of the machinery that controls SNARE complex assembly, Vps45 also plays a key role in determining the levels of its cognate SNARE proteins; another key factor in regulation of membrane traffic

Integrated Expression of Circulating miR375 and miR371 to Identify Teratoma and Active Germ Cell Malignancy Components in Malignant Germ Cell Tumors

Active germ cell malignancies express high levels of specific circulating micro-RNAs (miRNAs), including miR-371a-3p (miR371), which is undetectable in teratoma. Teratoma markers are urgently needed for theselection of patients and treatments because of the risk of malignant transformation and growing teratoma syndrome. To assess the accuracy of plasma miR375 alone or in combination with miR371 in detecting teratoma, 100 germ cell tumor patients, divided into two cohorts, were enrolled in a prospective multi-institutional study. In the discovery cohort, patients with pure teratoma and with no/low risk of harboring teratoma were compared; the validation cohort included patients with confirmed teratoma, active germ cell malignancy, or complete response after chemotherapy. The area under the receiver operating characteristic curve values for miR375, miR371, and miR371-miR375 were, respectively, 0.93 (95% confidence interval [CI]: 0.87-0.99), 0.59 (95% CI: 0.44-0.73), and 0.95 (95% CI: 0.90-0.99) in the discovery cohort and 0.55 (95% CI: 0.36-0.74), 0.74 (95% CI: 0.58-0.91), and 0.77 (95% CI: 0.62-0.93) in the validation cohort. Our study demonstrated that the plasma miR371-miR375 integrated evaluation is highly accurate to detect teratoma. PATIENT SUMMARY: The evaluation of two micro-RNAs (miR375-miR371) in the blood of patients with germ cell tumors is promising to predict teratoma. This test could be particularly relevant to the identification of teratoma in patients with postchemotherapy residual disease.info:eu-repo/semantics/publishedVersio

Small-Scale Fisheries Bycatch Jeopardizes Endangered Pacific Loggerhead Turtles

Background. Although bycatch of industrial-scale fisheries can cause declines in migratory megafauna including seabirds, marine mammals, and sea turtles, the impacts of small-scale fisheries have been largely overlooked. Small-scale fisheries occur in coastal waters worldwide, employing over 99 % of the world’s 51 million fishers. New telemetry data reveal that migratory megafauna frequent coastal habitats well within the range of small-scale fisheries, potentially producing high bycatch. These fisheries occur primarily in developing nations, and their documentation and management are limited or non-existent, precluding evaluation of their impacts on non-target megafauna. Principal Findings/Methodology. 30 North Pacific loggerhead turtles that we satellite-tracked from 1996–2005 ranged oceanwide, but juveniles spent 70 % of their time at a high use area coincident with small-scale fisheries in Baja California Sur, Mexico (BCS). We assessed loggerhead bycatch mortality in this area by partnering with local fishers to 1) observe two small-scale fleets that operated closest to the high use area and 2) through shoreline surveys for discarded carcasses. Minimum annual bycatch mortality in just these two fleets at the high use area exceeded 1000 loggerheads year 21, rivaling that of oceanwide industrial-scale fisheries, and threatening the persistence of this critically endangered population. As a result of fisher participation in this study and a bycatch awareness campaign, a consortium of local fishers and other citizens are working to eliminate their bycatch and to establish a national loggerhea