Letter to the Editor

Page et al. appear to have missed our point that the teratogenic effects of oil on fish derive from embryonic exposure to environmentally persistent 3- and 4-ring polycyclic aromatic hydrocarbons (PAHs). They regard our conclusions as incorrect because we failed to demonstrate causality or a clear dose-response relationship. As evidence for lack of causality, they indicate that our data were not replicated. However, our report was a companion paper to a similar one demonstrating PAH-induced teratogenesis in herring embryos, also in the low ppb. Current literature corroborates our data and careful consideration of our conclusion demonstrates that their inclusion of low molecular weight PAHs in their dose-response relationship is counter to their thesis that dose measures should only include toxic compounds. When we published this work 12 years ago, the concept that PAHs with high octanol-partition coefficient (KOW) were teratogenic at concentrations below their solubility was considered novel. Since then, the sensitivity of developing fish embryos to ppb concentrations of PAHs dissolved in water has been confirmed for fish embryos exposed to oiled sediments, dissolved mixtures of PAHs derived from oiled sediments, and specific high molecular weight PAHs dissolved in water; additional references will be found in the Supplemental Data. More recently, experiments involving specific PAHs with partition-controlled delivery systems also have demonstrated toxic effects at levels below aqueous solubility limits. At least eleven reports replicate our findings in seven different fish species and support our conclusion that accumulation of PAHs by embryos depends on the kinetics of the transfer of PAHs from oil to egg rather than PAH solubility

Seasonal presence and potential influence of humpback whales on wintering Pacific herring populations in the Gulf of Alaska

This study addressed the lack of recovery of Pacific herring (Clupea pallasii) in Prince William Sound, Alaska, in relation to humpback whale (Megaptera novaeangliae) predation.This study addressed the lack of recovery of Pacific herring (Clupea pallasii) in Prince William Sound, Alaska, in relation to humpback whale (Megaptera novaeangliae) predation. As humpback whales rebound from commercial whaling, their ability to influence their prey through top-down forcing increases. We compared the potential influence of foraging humpback whales on three herring populations in the coastal Gulf of Alaska: Prince William Sound, Lynn Canal, and Sitka Sound (133–147°W; 57–61°N) from 2007 to 2009. Information on whale distribution, abundance, diet and the availability of herring as potential prey were used to correlate populations of overwintering herring and humpback whales. In Prince William Sound, the presence of whales coincided with the peak of herring abundance, allowing whales to maximize the consumption of overwintering herring prior to their southern migration. In Lynn Canal and Sitka Sound peak attendance of whales occurred earlier, in the fall, before the herring had completely moved into the areas, hence, there was less opportunity for predation to influence herring populations. North Pacific humpback whales in the Gulf of Alaska may be experiencing nutritional stress from reaching or exceeding carrying capacity, or oceanic conditions may have changed sufficiently to alter the prey base. Intraspecific competition for food may make it harder for humpback whales to meet their annual energetic needs. To meet their energetic demands whales may need to lengthen their time feeding in the northern latitudes or by skipping the annual migration altogether. If humpback whales extended their time feeding in Alaskan waters during the winter months, the result would likely be an increase in herring predationAll humpback whale photographic data collected was authorized under scientific research permits 473-1700-01 and 782-1719 issued to Janice M. Straley and the National Marine Mammal Lab, respectively, from NOAA, Office of Protected Resources, WA, DC. In addition, this research was conducted with the authorization 08-07 of the Institutional Animal Care and Use Committee (IACUC), University of Alaska Fairbanks. Special thanks to D. Janka, and his knowledge of Prince William Sound and all the crew that joined us on our surveys. Also, thanks to Jennifer Cedarleaf, Ellen Chenoweth, Keith Cox, Suzie Teerlink, Fletcher Sewall, and others that assisted on surveys in Sitka Sound and Lynn Canal. Thanks to the Captains and crews of the NOAA Vessel John N Cobb, M/V Auklet, M/V Steller, and M/V Alaskan Adventurer, Heather Riley, Neil Dawson, Jennifer Cedarleaf, Ellen Chenoweth, Kate McLaughlin, Andy McLaughlin, Craig Matkin, Olga von Ziegesar, Fletcher Sewall, John Hudson, Keith Cox, Prince William Sound Science Center and Alaska Department of Fish and Game, Cordova. Reference to trade names does not imply endorsement by the National Marine Fisheries Service, NOAA. The findings and conclusions of this paper are those of the authors and do not necessarily represent the views of the National Marine Fisheries Service. The Exxon Valdez Oil Spill Trustee Council (award NA17NMF4720027) supported the research described in this paper. However, the findings and conclusions presented by the author(s) are their own and do not necessarily reflect the views or position the Trustee Council. The authors disclose there was no actual or potential conflict of interest including any financial, personal, or other relationships with other people or organizations within three years of beginning the submitted work that could inappropriately influence, or be perceived to influence, their work.Ye

Intracellular Proton Conductance of the Hepatitis C Virus p7 Protein and Its Contribution to Infectious Virus Production

The hepatitis C virus (HCV) p7 protein is critical for virus production and an attractive antiviral target. p7 is an ion channel when reconstituted in artificial lipid bilayers, but channel function has not been demonstrated in vivo and it is unknown whether p7 channel activity plays a critical role in virus production. To evaluate the contribution of p7 to organelle pH regulation and virus production, we incorporated a fluorescent pH sensor within native, intracellular vesicles in the presence or absence of p7 expression. p7 increased proton (H+) conductance in vesicles and was able to rapidly equilibrate H+ gradients. This conductance was blocked by the viroporin inhibitors amantadine, rimantadine and hexamethylene amiloride. Fluorescence microscopy using pH indicators in live cells showed that both HCV infection and expression of p7 from replicon RNAs reduced the number of highly acidic (pH<5) vesicles and increased lysosomal pH from 4.5 to 6.0. These effects were not present in uninfected cells, sub-genomic replicon cells not expressing p7, or cells electroporated with viral RNA containing a channel-inactive p7 point mutation. The acidification inhibitor, bafilomycin A1, partially restored virus production to cells electroporated with viral RNA containing the channel inactive mutation, yet did not in cells containing p7-deleted RNA. Expression of influenza M2 protein also complemented the p7 mutant, confirming a requirement for H+ channel activity in virus production. Accordingly, exposure to acid pH rendered intracellular HCV particles non-infectious, whereas the infectivity of extracellular virions was acid stable and unaffected by incubation at low pH, further demonstrating a key requirement for p7-induced loss of acidification. We conclude that p7 functions as a H+ permeation pathway, acting to prevent acidification in otherwise acidic intracellular compartments. This loss of acidification is required for productive HCV infection, possibly through protecting nascent virus particles during an as yet uncharacterized maturation process

The structure of the tetrasialoganglioside from human brain

Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle- age onset. In nine families, we identified heterozygous C- terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease activity but lose normal perinuclear localization. These data have implications for the maintenance of vascular integrity in the degenerative cerebral microangiopathies leading to stroke and dementias

A pair production telescope for medium-energy gamma-ray polarimetry

We describe the science motivation and development of a pair production telescope for medium-energy (∼5–200 MeV) gamma-ray polarimetry. Our instrument concept, the Advanced Energetic Pair Telescope (AdEPT), takes advantage of the Three-Dimensional Track Imager, a low-density gaseous time projection chamber, to achieve angular resolution within a factor of two of the pair production kinematics limit (∼0.6° at 70 MeV), continuum sensitivity comparable with the Fermi-LAT front detector (<3 × 10−6 MeV cm−2 s−1 at 70 MeV), and minimum detectable polarization less than 10% for a 10 mCrab source in 106 s.submittedVersionFil: Hunter, Stanley D. National Aeronautics and Space Administration. Goddard Space Flight Center; Estados Unidos de América.Fil: Bloser, Peter F. University of New Hampshire. Institute for the Study of Earth, Oceans, and Space. Space Science Center; Estados Unidos de América.Fil: Depaola, Gerardo Osvaldo. Universidad Nacional de Córdoba. Facultad de Matemática, Astronomía y Física; Argentina.Fil: Dion, Michael P. Department of Energy. Office of Science. Pacific Northwest National Laboratory; Estados Unidos de América.Fil: DeNolfo, Georgia A. National Aeronautics and Space Administration. Goddard Space Flight Center; Estados Unidos de América.Fil: Hanu, Andrei. National Aeronautics and Space Administration. Goddard Space Flight Center; Estados Unidos de América.Fil: Iparraguirre, Lorenzo Marcos. Universidad Nacional de Córdoba. Facultad de Matemática, Astronomía y Física; Argentina.Fil: Legere, Jason. University of New Hampshire. Institute for the Study of Earth, Oceans, and Space. Space Science Center; Estados Unidos de América.Fil: Longo, Francesco. Università Degli Studi de Trieste. Dipartimento di fisica; Italia.Fil: McConnell, Mark L. University of New Hampshire. Institute for the Study of Earth, Oceans, and Space. Space Science Center; Estados Unidos de América.Fil: Nowicki, Suzanne F. National Aeronautics and Space Administration. Goddard Space Flight Center; Estados Unidos de América.Fil: Nowicki, Suzanne F. University of Maryland, Baltimore County. Department of Physics; Estados Unidos de América.Fil: Ryan, James M. University of New Hampshire. Institute for the Study of Earth, Oceans, and Space. Space Science Center; Estados Unidos de América.Fil: Son, Seunghee. National Aeronautics and Space Administration. Goddard Space Flight Center; Estados Unidos de América.Fil: Son, Seunghee. University of Maryland, Baltimore County. Department of Physics; Estados Unidos de América.Fil: Stecker, Floyd W. National Aeronautics and Space Administration. Goddard Space Flight Center; Estados Unidos de América.Física de Partículas y Campo

Diazoxide Promotes Oligodendrocyte Precursor Cell Proliferation and Myelination

Several clinical conditions are associated with white matter injury, including periventricular white matter injury (PWMI), which is a form of brain injury sustained by preterm infants. It has been suggested that white matter injury in this condition is due to altered oligodendrocyte (OL) development or death, resulting in OL loss and hypomyelination. At present drugs are not available that stimulate OL proliferation and promote myelination. Evidence suggests that depolarizing stimuli reduces OL proliferation and differentiation, whereas agents that hyperpolarize OLs stimulate OL proliferation and differentiation. Considering that the drug diazoxide activates K(ATP) channels to hyperpolarize cells, we tested if this compound could influence OL proliferation and myelination.Studies were performed using rat oligodendrocyte precursor cell (OPC) cultures, cerebellar slice cultures, and an in vivo model of PWMI in which newborn mice were exposed to chronic sublethal hypoxia (10% O(2)). We found that K(ATP) channel components Kir 6.1 and 6.2 and SUR2 were expressed in oligodendrocytes. Additionally, diazoxide potently stimulated OPC proliferation, as did other K(ATP) activators. Diazoxide also stimulated myelination in cerebellar slice cultures. We also found that diazoxide prevented hypomyelination and ventriculomegaly following chronic sublethal hypoxia.These results identify KATP channel components in OLs and show that diazoxide can stimulate OL proliferation in vitro. Importantly we find that diazoxide can promote myelination in vivo and prevent hypoxia-induced PWMI