Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants

IC80 1.5 to 34.5 nanograms per milliliter). We define the structural and functional determinants of binding for all four VOC-targeting antibodies and show that combinations of two antibodies decrease the in vitro generation of escape mutants, suggesting their potential in mitigating resistance development.The emergence of highly transmissible SARS-CoV-2 variants of concern (VOCs) that are resistant to therapeutic antibodies highlights the need for continuing discovery of broadly reactive antibodies. We identified four receptor binding domain-targeting antibodies from three early-outbreak convalescent donors with potent neutralizing activity against 23 variants, including the B.1.1.7, B.1.351, P.1, B.1.429, B.1.526, and B.1.617 VOCs. Two antibodies are ultrapotent, with subnanomolar neutralization titers [half-maximal inhibitory concentration (IC50) 0.3 to 11.1 nanograms per millilite

Orexin-A activates locus coeruleus cell firing and increases arousal in the rat

Original article can be found at: http://www.pnas.org/ Copyright by The National Academy of Sciences [Full text of this article is not available in the UHRA]Peer reviewe

Remdesivir induced viral RNA and subgenomic RNA suppression, and evolution of viral variants in SARS-CoV-2 infected patients

AbstractWhile changes in SARS-CoV-2 viral load over time have been documented, detailed information on the impact of remdesivir and how it might alter intra-host viral evolution is limited. Sequential viral loads and deep sequencing of SARS-CoV-2 recovered from the upper respiratory tract of hospitalised children revealed that remdesivir treatment suppressed viral RNA levels in one patient but not in a second infected with an identical strain. Evidence of drug resistance to explain this difference was not found. Reduced levels of subgenomic (sg) RNA during treatment of the second patient, suggest an additional effect of remdesivir on viral replication that is independent of viral RNA levels. Haplotype reconstruction uncovered persistent SARS-CoV-2 variant genotypes in four patients. We conclude that these are likely to have arisen from within-host evolution, and not co-transmission, although superinfection cannot be excluded in one case. Sample-to-sample heterogeneity in the abundances of variant genotypes is best explained by the presence of discrete viral populations in the lung with incomplete population sampling in diagnostic swabs. Such compartmentalisation is well described in serious lung infections caused by influenza and Mycobacterium tuberculosis and has been associated with poor drug penetration, suboptimal treatment and drug resistance. Our data provide evidence that remdesivir is able to suppress SARS-CoV-2 replication in vivo but that its efficacy may be compromised by factors reducing penetration into the lung. Based on data from influenza and Mycobacterium tuberculosis lung infections we conclude that early use of remdesivir combined with other agents should now be evaluated.Summary SentenceDeep sequencing of longitudinal samples from SARS-CoV-2 infected paediatric patients identifies evidence of remdesivir-associated inhibition of viral replication in vivo and uncovers evidence of within host evolution of distinct viral genotypes.</jats:sec

The importance of changing oceanography in controlling late Quaternary carbonate sedimentation on a high-energy, tropical, oceanic ramp: north-western Australia

The North West Shelf is an ocean-facing carbonate ramp that lies in a warm-water setting adjacent to an arid hinterland of moderate to low relief. The sea floor is strongly affected by cyclonic storms, long-period swells and large internal tides, resulting in preferentially accumulating coarse-grained sediments. Circulation is dominated by the south-flowing, low-salinity Leeuwin Current, upwelling associated with the Indian Ocean Gyre, seaward-flowing saline bottom waters generated by seasonal evaporation, and flashy fluvial discharge. Sediments are palimpsest, a variable mixture of relict, stranded and Holocene grains. Relict intraclasts, both skeletal and lithic, interpreted as having formed during sea-level highstands of Marine Isotope Stages (MIS) 3 and 4, are now localized to the mid-ramp. The most conspicuous stranded particles are ooids and peloids, which 14C dating shows formed at 15·4-12·7 Ka, in somewhat saline waters during initial stages of post-Last Glacial Maximum (LGM) sea-level rise. It appears that initiation of Leeuwin Current flow with its relatively less saline, but oceanic waters arrested ooid formation such that subsequent benthic Holocene sediment is principally biofragmental, with sedimentation localized to the inner ramp and a ridge of planktic foraminifera offshore. Inner-ramp deposits are a mixture of heterozoan and photozoan elements. Depositional facies reflect episodic environmental perturbation by riverine-derived sediments and nutrients, resulting in a mixed habitat of oligotrophic (coral reefs and large benthic foraminifera) and mesotrophic (macroalgae and bryozoans) indicators. Holocene mid-ramp sediment is heterozoan in character, but sparse, most probably because of the periodic seaward flow of saline bottom waters generated by coastal evaporation. Holocene outer-ramp sediment is mainly pelagic, veneering shallow-water sediments of Marine Isotope Stage 2, including LGM deposits. Phosphate accumulations at ≈ 200 m. water depth suggest periodic upwelling or Fe-redox pumping, whereas enhanced near-surface productivity, probably associated with the interaction between the Leeuwin Current and Indian Ocean surface water, results in a linear ridge of pelagic sediment at ≈ 140 m. water depth. This ramp depositional system in an arid climate has important applications for the geological record: inner-ramp sediments can contain important heterozoan elements, mid-ramp sediments with bedforms created by internal tides can form in water depths exceeding 50 m, saline outflow can arrest or dramatically slow mid-ramp sedimentation mimicking maximum flooding intervals, and outer-ramp planktic productivity can generate locally important fine-grained carbonate sediment bodies. Changing oceanography during sea-level rise can profoundly affect sediment composition, sedimentation rate and packaging. © 2004 International Association of Sedimentologists