The first Cenozoic ice sheets initiated in Antarctica from the Gamburtsev Subglacial Mountains and other highlands as a result of rapid global cooling ∼34 million years ago. In the subsequent 20 ...million years, at a time of declining atmospheric carbon dioxide concentrations and an evolving Antarctic circumpolar current, sedimentary sequence interpretation and numerical modelling suggest that cyclical periods of ice-sheet expansion to the continental margin, followed by retreat to the subglacial highlands, occurred up to thirty times. These fluctuations were paced by orbital changes and were a major influence on global sea levels. Ice-sheet models show that the nature of such oscillations is critically dependent on the pattern and extent of Antarctic topographic lowlands. Here we show that the basal topography of the Aurora Subglacial Basin of East Antarctica, at present overlain by 2-4.5 km of ice, is characterized by a series of well-defined topographic channels within a mountain block landscape. The identification of this fjord landscape, based on new data from ice-penetrating radar, provides an improved understanding of the topography of the Aurora Subglacial Basin and its surroundings, and reveals a complex surface sculpted by a succession of ice-sheet configurations substantially different from today's. At different stages during its fluctuations, the edge of the East Antarctic Ice Sheet lay pinned along the margins of the Aurora Subglacial Basin, the upland boundaries of which are currently above sea level and the deepest parts of which are more than 1 km below sea level. Although the timing of the channel incision remains uncertain, our results suggest that the fjord landscape was carved by at least two iceflow regimes of different scales and directions, each of which would have over-deepened existing topographic depressions, reversing valley floor slopes.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Survival in high-risk pediatric neuroblastoma has remained around 50% for the last 20 years, with immunotherapies and targeted therapies having had minimal impact. Here, we identify the small ...molecule CX-5461 as selectively cytotoxic to high-risk neuroblastoma and synergistic with low picomolar concentrations of topoisomerase I inhibitors in improving survival in vivo in orthotopic patient-derived xenograft neuroblastoma mouse models. CX-5461 recently progressed through phase I clinical trial as a first-in-human inhibitor of RNA-POL I. However, we also use a comprehensive panel of in vitro and in vivo assays to demonstrate that CX-5461 has been mischaracterized and that its primary target at pharmacologically relevant concentrations, is in fact topoisomerase II beta (TOP2B), not RNA-POL I. This is important because existing clinically approved chemotherapeutics have well-documented off-target interactions with TOP2B, which have previously been shown to cause both therapy-induced leukemia and cardiotoxicity-often-fatal adverse events, which can emerge several years after treatment. Thus, while we show that combination therapies involving CX-5461 have promising anti-tumor activity in vivo in neuroblastoma, our identification of TOP2B as the primary target of CX-5461 indicates unexpected safety concerns that should be examined in ongoing phase II clinical trials in adult patients before pursuing clinical studies in children.
The ARTEMIS under‐ice AUV docking system Kimball, Peter W.; Clark, Evan B.; Scully, Mark ...
Journal of field robotics,
March 2018, Volume:
35, Issue:
2
Journal Article
Peer reviewed
The ARTEMIS docking system demonstrates autonomous docking capability applicable to robotic exploration of sub‐ice oceans and sub‐glacial lakes on planetary bodies, as well as here on Earth. In these ...applications, melted or drilled vertical access shafts restrict vehicle geometry as well as the in‐water infrastructure that may be deployed. The ability of the vehicle to return reliably and precisely to the access point is critical for data return, battery charging, and/or vehicle recovery. This paper presents the mechanical, sensor, and software components that make up the ARTEMIS docking system, as well as results from field deployment of the system to McMurdo Sound, Antarctica in the austral spring of 2015. The mechanical design of the system allows the vehicle to approach the dock from any direction and to pitch up after docking for recovery through a vertical access shaft. It uses only a small volume of in‐water equipment and may be deployed through a narrow vertical access shaft. The software of the system reduces position estimation error with a hierarchical combination of dead reckoning, acoustic aiding, and machine vision. The system provides critical operational robustness, enabling the vehicle to return autonomously and precisely to the access shaft and latch to the dock with no operator input.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
•Describes a multinational outbreak of listeriosis linked to enoki mushrooms.•Emphasizes the need for and impact of international collaboration and data sharing.•Traceback, laboratory, and ...epidemiologic data helped identify the outbreak source.•Highlights challenges of responding to multinational foodborne illness outbreaks.
Keeping the global food supply safe necessitates international collaborations between countries. Health and regulatory agencies routinely communicate during foodborne illness outbreaks, allowing partners to share investigational evidence. A 2016–2020 outbreak of Listeria monocytogenes infections linked to imported enoki mushrooms required a multinational collaborative investigation among the United States, Canada, Australia, and France. Ultimately, this outbreak included 48 ill people, 36 in the United States and 12 in Canada, and was linked to enoki mushrooms sourced from one manufacturer located in the Republic of Korea. Epidemiologic, laboratory, and traceback evidence led to multiple regulatory actions, including extensive voluntary recalls by three firms in the United States and one firm in Canada. In the United States and Canada, the Korean manufacturer was placed on import alert while other international partners provided information about their respective investigations and advised the public not to eat the recalled enoki mushrooms. The breadth of the geographic distribution of this outbreak emphasizes the global reach of the food industry. This investigation provides a powerful example of the impact of national and international coordination of efforts to respond to foodborne illness outbreaks and protect consumers. It also demonstrates the importance of fast international data sharing and collaboration in identifying and stopping foodborne outbreaks in the global community. Additionally, it is a meaningful example of the importance of food sampling, testing, and integration of sequencing results into surveillance databases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Background:
β-glucosylceramides (βGlcCers) are elevated in allergic mouse dams and are necessary and sufficient to induce allergy predisposition in offspring. βGlcCers increase dendritic ...cell (DC) numbers in the fetal liver and pup lungs. We hypothesize that these lung DCs predispose offspring to allergic lung responses. We also hypothesize that βGlcCers induce elevated pro-allergy IRF4+ DC numbers during fetal hematopoiesis.
Methods:
Pregnant mice were injected with a mixture of βGlcCers known to predispose offspring to allergic asthma. DCs were assayed by flow cytometry. In another approach, lung DCs from pups of non-allergic dams or allergy predisposed pups born to allergic dams were transferred to lungs of pups of non-allergic dams. Recipient pups received suboptimal sensitization and airway allergen challenge.
Results:
An increase in number of IRF4+ DCs was observed in fetal livers when dams received βGlcCers compared to fetal livers from vehicle-injected dams. Higher numbers of IRF4+ DCs were in the lungs of pups born to allergic dams compared to pups born to non-allergic dams. Transfer of CD45.1 lung DCs from pups born to allergic dams to lungs of CD45.2 pups born to non-allergic dams induced allergy predisposition in the recipients compared to lung DC transfers from pups born to non-allergic dams. Furthermore, elevated numbers of endogenous CD45.2 IRF4+ lung DCs were observed in allergen-challenged pups that received lung DCs from pups born to allergic dams.
Conclusions:
These results suggest that βGlcCer induces increased numbers of pro-allergy IRF4+ DCs during fetal hematopoiesis. These results further suggest that lung DCs from pups born to allergic dams are induce allergen responsiveness and higher lung IRF4+ DC numbers.
Supported by grants from NIH (R01AI127695 and U01AI131337)
A 1,000-bed hospital ship designed for trauma patients was deployed to the Middle East with the objectives of preparing for large numbers of casualties resulting from Operation Desert Storm from ...conventional, chemical, and biological weapons. Plans for receipt and decontamination of casualties, triage, and optimal utilization of the 1,000-bed facility were developed. Mass casualty drills were conducted, involving all aspects of patient care from the flight deck to the wards. Trauma and critical care registries were developed to collect casualty data that could then be analyzed for specific military purposes and compared with current civilian registries. Attempts were made to identify the advances in shock resuscitation, systems management, and operative treatment from the civilian community that could be applied to care of combat casualties. Difficulties with accomplishing these objectives included limited trauma experience and supplies and poorly defined medical regulating and evacuation policies. The development of these programs, as well as the unique difficulties encountered, are discussed.
As an essential enzyme of SARS-CoV-2, the COVID-19 pathogen, main protease (MPro) is a viable target to develop antivirals for the treatment of COVID-19. By varying chemical compositions at both P2 ...and P3 positions and the N-terminal protection group, we synthesized 18 tripeptidyl MPro inhibitors that contained also an aldehyde warhead and β-(S-2-oxopyrrolidin-3-yl)-alaninal at the P1 position. Systematic characterizations of these inhibitors were conducted, including their in vitro enzymatic inhibition potency, X-ray crystal structures of their complexes with MPro, their inhibition of MPro transiently expressed in 293T cells, and cellular toxicity and SARS-CoV-2 antiviral potency of selected inhibitors. These inhibitors have a large variation of determined in vitro enzymatic inhibition IC50 values that range from 4.8 to 650 nM. The determined in vitro enzymatic inhibition IC50 values reveal that relatively small side chains at both P2 and P3 positions are favorable for achieving high in vitro MPro inhibition potency, the P3 position is tolerable toward unnatural amino acids with two alkyl substituents on the α-carbon, and the inhibition potency is sensitive toward the N-terminal protection group. X-ray crystal structures of MPro bound with 16 inhibitors were determined. In all structures, the MPro active site cysteine interacts covalently with the aldehyde warhead of the bound inhibitor to form a hemithioacetal that takes an S configuration. For all inhibitors, election density around the N-terminal protection group is weak indicating possible flexible binding of this group to MPro. In MPro, large structural variations were observed on residues N142 and Q189. Unlike their high in vitro enzymatic inhibition potency, most inhibitors showed low potency to inhibit MPro that was transiently expressed in 293T cells. Inhibitors that showed high potency to inhibit MPro transiently expressed in 293T cells all contain O-tert-butyl-threonine at the P3 position. These inhibitors also exhibited relatively low cytotoxicity and high antiviral potency. Overall, our current and previous studies indicate that O-tert-butyl-threonine at the P3 site is a key component to achieve high cellular and antiviral potency for tripeptidyl aldehyde inhibitors of MPro.
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•New highly potent SARS-CoV-2 MPro inhibitors (IC50 value as low as 4.8 nM).•Inhibitors exhibiting high cellular MPro inhibition potency (EC50 as low as 56 nM).•O-tert-butyl-threonine at P3 site is critical for high cellular and antiviral potency.•16 Crystal structures of MPro-inhibitor complexes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Melting and refreezing processes in the firn of the Devon Ice Cap control meltwater infiltration and runoff across the ice cap, but their full spatial extent and effect on near-surface structure is ...difficult to measure with surface-based traverses or existing satellite remote sensing. Here, we derive the coherent component of the near-surface return from airborne ice-penetrating radar surveys over the Devon Ice Cap, Canadian Arctic, to characterize firn containing centimeter- to meter-thick ice layers (i.e., ice slabs) formed from refrozen meltwater in firn. We assess the use of dual-frequency airborne ice-penetrating radar to characterize the spatial and vertical near-surface structure of the Devon Ice Cap by leveraging differences in range resolution of the radar systems. Comparison with reflectivities using a thin layer reflectivity model, informed by surface-based radar and firn core measurements, indicates that the coherent component is sensitive to the near-surface firn structure composed of quasi-specular ice and firn layers, limited by the bandwidth-constrained radar range resolution. Our results suggest that average ice slab thickness throughout the Devon Ice Cap percolation zone ranges from 4.2 to 5.6 m. This implies conditions that can enable lateral meltwater runoff and potentially contribute to the total surface runoff routed through supraglacial rivers down glacier. Together with the incoherent component of the surface return previously studied, our dual-frequency approach provides an alternative method for characterizing bulk firn properties, particularly where high-resolution radar data are not available.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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