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.
We use models constrained by remotely sensed data from Pine Island and Thwaites Glaciers, West Antarctica, to infer basal properties that are difficult to observe directly. The results indicate ...strong basal melting in areas upstream of the grounding lines of both glaciers, where the ice flow is fast and the basal shear stress is large. Farther inland, we find that both glaciers have ‘mixed’ bed conditions, with extensive areas of both bedrock and weak till. In particular, there are weak areas along much of Pine Island Glacier’s main trunk that could prove unstable if it retreats past the band of strong bed just above its current grounding line. In agreement with earlier studies, our forward ice-stream model shows a strong sensitivity to small perturbations in the grounding line position. These results also reveal a large sensitivity to the assumed bed (sliding or deforming) model, with non-linear sliding laws producing substantially greater dynamic response than earlier simulations that assume a linear-viscous till rheology. Finally, comparison indicates that our results using a plastic bed are compatible with the limited observational constraints and theoretical work that suggests an upper bound exists on maximum basal shear stress.
This paper presents focused synthetic aperture radar (SAR) processing of airborne radar sounding data acquired with the High-Capability Radar Sounder system at 60 MHz. The motivation is to improve ...basal reflection analysis for water detection and to improve layer detection and tracking. The processing and reflection analyses are applied to data from Kamb Ice Stream, West Antarctica. The SAR processor correlates the radar data with reference echoes from subsurface point targets. The references are 1-D responses limited by the pulse nadir footprint or 2-D responses that include echo tails. Unfocused SAR and incoherent integration are included for comparison. Echoes are accurately preserved from along-track slopes up to about 0.5deg for unfocused SAR, 3deg for 1-D correlations, and 10deg for 2-D correlations. The noise/clutter levels increase from unfocused SAR to 1-D and 2-D correlations, but additional gain compensates at the basal interface. The basal echo signal-to-noise ratio improvement is typically about 5 dB, and up to 10 dB for 2-D correlations in rough regions. The increased noise degrades the clarity of internal layers in the 2-D correlations, but detection of layers with slopes greater than 3deg is improved. Reflection coefficients are computed for basal water detection, and the results are compared for the different processing methods. There is a significant increase in the detected water from unfocused SAR to 1-D correlations, indicating that substantial basal water exists on moderately sloped interfaces. Very little additional water is detected from the 2-D correlations. The results from incoherent integration are close to the focused SAR results, but the noise/clutter levels are much greater.
Airborne radar sounding over the Thwaites Glacier (TG) catchment and its surroundings provides the first comprehensive view of subglacial topography in this dynamic part of the West Antarctic Ice ...Sheet (WAIS) and reveals that TG is underlain by a single, broad basin fed by a dendritic pattern of valleys, while Smith Glacier lies within an extremely deep, narrow trench. Subglacial topography in the TG catchment slopes inland from a broad, low‐relief coastal sill to the thickest ice of the WAIS and makes deep connections to both Pine Island Glacier and the Ross Sea Embayment enabling dynamic interactions across the WAIS during deglaciation. Simple isostatic rebound modeling shows that most of this landscape would be submarine after deglaciation, aside from an island chain near the present‐day Ross‐Amundsen ice divide. The lack of topographic confinement along TG's eastern margin implies that it may continue to widen in response to grounding line retreat.
Predictions about future changes in the Amundsen Sea sector of the West Antarctic ice sheet (WAIS) have been hampered by poorly known subglacial topography. Extensive airborne survey has allowed us ...to derive improved subglacial topography for the Pine Island Glacier basin. The trunk of this glacier lies in a narrow, 250‐km long, 500‐m deep sub‐glacial trough, suggesting a long‐lived and constrained ice stream. Two tributaries lie in similar troughs, others lie in less defined, shallower troughs. The lower basin of the glacier is surrounded by bedrock, which, after deglaciation and isostatic rebound, could rise above sea level. This feature would impede ice‐sheet collapse initiated near the grounding line of this glacier, and prevent its progress into the deepest portions of WAIS. The inland‐slope of the bed beneath the trunk of the glacier, however, confirms potential instability of the lower basin, containing sufficient ice to raise global sea by ∼24 cm.
A family of anti-apoptotic regulators known as IAP (inhibitor of apoptosis) proteins interact with multiple cellular partners and inhibit apoptosis induced by a variety of stimuli. c-IAP (cellular ...IAP) 1 and 2 are recruited to TNFR1 (tumour necrosis factor receptor 1)-associated signalling complexes, where they mediate receptor-induced NF-kappaB (nuclear factor kappaB) activation. Additionally, through their E3 ubiquitin ligase activities, c-IAP1 and c-IAP2 promote proteasomal degradation of NIK (NF-kappaB-inducing kinase) and regulate the non-canonical NF-kappaB pathway. In the present paper, we describe a novel ubiquitin-binding domain of IAPs. The UBA (ubiquitin-associated) domain of IAPs is located between the BIR (baculovirus IAP repeat) domains and the CARD (caspase activation and recruitment domain) or the RING (really interesting new gene) domain of c-IAP1 and c-IAP2 or XIAP (X-linked IAP) respectively. The c-IAP1 UBA domain binds mono-ubiquitin and Lys(48)- and Lys(63)-linked polyubiquitin chains with low-micromolar affinities as determined by surface plasmon resonance or isothermal titration calorimetry. NMR analysis of the c-IAP1 UBA domain-ubiquitin interaction reveals that this UBA domain binds the classical hydrophobic patch surrounding Ile(44) of ubiquitin. Mutations of critical amino acid residues in the highly conserved MGF (Met-Gly-Phe) binding loop of the UBA domain completely abrogate ubiquitin binding. These mutations in the UBA domain do not overtly affect the ubiquitin ligase activity of c-IAP1 or the participation of c-IAP1 and c-IAP2 in the TNFR1 signalling complex. Treatment of cells with IAP antagonists leads to proteasomal degradation of c-IAP1 and c-IAP2. Deletion or mutation of the UBA domain decreases this degradation, probably by diminishing the interaction of the c-IAPs with the proteasome. These results suggest that ubiquitin binding may be an important mechanism for rapid turnover of auto-ubiquitinated c-IAP1 and c-IAP2.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma low-density lipoprotein cholesterol (LDL-C) levels by promoting the degradation of hepatic LDL receptors (LDLRs). Current ...therapeutic approaches use antibodies that disrupt PCSK9 binding to LDLR to reduce circulating LDL-C concentrations or siRNA that reduces PCSK9 synthesis and thereby levels in circulation. Recent reports describe small molecules that, like therapeutic antibodies, interfere with PCSK9 binding to LDLR. We report an alternative approach to decrease circulating PCSK9 levels by accelerating PCSK9 clearance and degradation using heterobifunctional molecules that simultaneously bind to PCSK9 and the asialoglycoprotein receptor (ASGPR). Various formats, including bispecific antibodies, antibody-small molecule conjugates, and heterobifunctional small molecules, demonstrate binding in vitro and accelerated PCSK9 clearance in vivo. These molecules showcase a new approach to PCSK9 inhibition, targeted plasma protein degradation (TPPD), and demonstrate the feasibility of heterobifunctional small molecule ligands to accelerate the clearance and degradation of pathogenic proteins in circulation.
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•ASGPR-targeting heterobifunctional molecules lead to the clearance of PCSK9 in vivo•PCSK9 is cleared by bispecific antibodies, antibody conjugates, and small molecules•PCSK9 clearance requires binding to both the ASGPR and to PCSK9•Heterobifunctional molecules do not lead to significant degradation of LDLR or ASGPR
Bagdanoff et al. describe heterobifunctional molecules that mediate in vivo clearance of the pathologically relevant plasma protein PCSK9 in mice, demonstrating rapid, ASGPR-dependent clearance using multiple classes of heterobifunctional constructs including bispecific antibodies, antibody-drug conjugates, and small molecules.
Myocardial salvage is often suboptimal after percutaneous coronary intervention in ST-segment elevation myocardial infarction. Posthoc subgroup analysis from a previous trial (AMIHOT I) suggested ...that intracoronary delivery of supersaturated oxygen (SSO(2)) may reduce infarct size in patients with large ST-segment elevation myocardial infarction treated early.
A prospective, multicenter trial was performed in which 301 patients with anterior ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention within 6 hours of symptom onset were randomized to a 90-minute intracoronary SSO(2) infusion in the left anterior descending artery infarct territory (n=222) or control (n=79). The primary efficacy measure was infarct size in the intention-to-treat population (powered for superiority), and the primary safety measure was composite major adverse cardiovascular events at 30 days in the intention-to-treat and per-protocol populations (powered for noninferiority), with Bayesian hierarchical modeling used to allow partial pooling of evidence from AMIHOT I. Among 281 randomized patients with tc-99m-sestamibi single-photon emission computed tomography data in AMIHOT II, median (interquartile range) infarct size was 26.5% (8.5%, 44%) with control compared with 20% (6%, 37%) after SSO(2). The pooled adjusted infarct size was 25% (7%, 42%) with control compared with 18.5% (3.5%, 34.5%) after SSO(2) (P(Wilcoxon)=0.02; Bayesian posterior probability of superiority, 96.9%). The Bayesian pooled 30-day mean (+/-SE) rates of major adverse cardiovascular events were 5.0+/-1.4% for control and 5.9+/-1.4% for SSO(2) by intention-to-treat, and 5.1+/-1.5% for control and 4.7+/-1.5% for SSO(2) by per-protocol analysis (posterior probability of noninferiority, 99.5% and 99.9%, respectively).
Among patients with anterior ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention within 6 hours of symptom onset, infusion of SSO(2) into the left anterior descending artery infarct territory results in a significant reduction in infarct size with noninferior rates of major adverse cardiovascular events at 30 days. Clinical Trial Registration- clinicaltrials.gov Identifier: NCT00175058.
Subglacial lakes in East Antarctica can be separated into four categories specified by radar reflection properties. Definite lakes are brighter than their surroundings by at least 2 dB (relatively ...bright) and both are consistently reflective (specular) and have a reflection coefficient greater than −10 dB (absolutely bright). Dim lakes are relatively bright and specular but not absolutely bright, indicating nonsteady ice dynamics. Fuzzy lakes are both relatively and absolutely bright, but not specular, and may indicate saturated sediments or “swamps.” Indistinct lakes are absolutely bright and specular but no brighter than their surroundings. Lakes themselves and the different classes of lakes are not arranged randomly throughout Antarctica but are clustered around ice divides, ice stream onsets, and prominent bedrock troughs, with each cluster demonstrating a different characteristic lake classification distribution. The lake classification algorithm expands on previous studies and demonstrates a novel way to characterize ice‐water interactions in East Antarctica.
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