Sensitivity of melting, freezing and marine ice beneath Larsen C Ice Shelf to changes in ocean forcing

Observations of surface lowering on Larsen C Ice Shelf (LCIS), Antarctica, have prompted concern about its stability. In this study, an ocean model is used to investigate the extent to which changes in ocean forcing may have influenced ice loss and the distribution of stabilising marine ice beneath LCIS. The model uses a new bathymetry, containing a southern seabed trough discovered using seismic observations. The modelled extent of marine ice, thought to stabilise LCIS, is in good agreement with observations. Experiments applying idealised ocean warming yield an increase in melting over the southern trough. This is inconsistent with lowering observed in northern LCIS, suggesting oceanic forcing is not responsible for that signal. The marine ice extent and thickness reduces significantly under ocean warming, implying a high sensitivity of LCIS stability to changes in ocean forcing. This result could have wide implications for other cold-water ice shelves around Antarctica

Hematopoietic Cell–Restricted Deletion of CD36 Reduces High-Fat Diet–Induced Macrophage Infiltration and Improves Insulin Signaling in Adipose Tissue

OBJECTIVE: The fatty acid translocase and scavenger receptor CD36 is important in the recognition and uptake of lipids. Accordingly, we hypothesized that it plays a role in saturated fatty acid-induced macrophage lipid accumulation and proinflammatory activation. RESEARCH DESIGN AND METHODS: In vitro, the effect of CD36 inhibition and deletion in lipid-induced macrophage inflammation was assessed using the putative CD36 inhibitor, sulfosuccinimidyl oleate (SSO), and bone marrow-derived macrophages from mice with (CD36KO) or without (wild-type) global deletion of CD36. To investigate whether deletion of macrophage CD36 would improve insulin sensitivity in vivo, wild-type mice were transplanted with bone marrow from CD36KO or wild-type mice and then fed a standard or high-fat diet (HFD) for 20 weeks. RESULTS: SSO treatment markedly reduced saturated fatty acid-induced lipid accumulation and inflammation in RAW264.7 macrophages. Mice harboring CD36-specific deletion in hematopoietic-derived cells (HSC CD36KO) fed an HFD displayed improved insulin signaling and reduced macrophage infiltration in adipose tissue compared with wild-type mice, but this did not translate into protection against HFD-induced whole-body insulin resistance. Contrary to our hypothesis and our results using SSO in RAW264.7 macrophages, neither saturated fatty acid-induced lipid accumulation nor inflammation was reduced when comparing CD36KO with wild-type bone marrow-derived macrophages. CONCLUSIONS: Although CD36 does not appear important in saturated fatty acid-induced macrophage lipid accumulation, our study uncovers a novel role for CD36 in the migration of proinflammatory phagocytes to adipose tissue in obesity, with a concomitant improvement in insulin action

Hsp90 orchestrates transcriptional regulation by Hsf1 and cell wall remodelling by MAPK signalling during thermal adaptation in a pathogenic yeast

Acknowledgments We thank Rebecca Shapiro for creating CaLC1819, CaLC1855 and CaLC1875, Gillian Milne for help with EM, Aaron Mitchell for generously providing the transposon insertion mutant library, Jesus Pla for generously providing the hog1 hst7 mutant, and Cathy Collins for technical assistance.Peer reviewedPublisher PD

Outcomes in pediatric studies of medium-chain acyl-coA dehydrogenase (MCAD) deficiency and phenylketonuria (PKU): a review.

BACKGROUND: Inherited metabolic diseases (IMDs) are a group of individually rare single-gene diseases. For many IMDs, there is a paucity of high-quality evidence that evaluates the effectiveness of clinical interventions. Clinical effectiveness trials of IMD interventions could be supported through the development of core outcome sets (COSs), a recommended minimum set of standardized, high-quality outcomes and associated outcome measurement instruments to be incorporated by all trials in an area of study. We began the process of establishing pediatric COSs for two IMDs, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency and phenylketonuria (PKU), by reviewing published literature to describe outcomes reported by authors, identify heterogeneity in outcomes across studies, and assemble a candidate list of outcomes. METHODS: We used a comprehensive search strategy to identify primary studies and guidelines relevant to children with MCAD deficiency and PKU, extracting study characteristics and outcome information from eligible studies including outcome measurement instruments for select outcomes. Informed by an established framework and a previously published pediatric COS, outcomes were grouped into five, mutually-exclusive, a priori core areas: growth and development, life impact, pathophysiological manifestations, resource use, and death. RESULTS: For MCAD deficiency, we identified 83 outcomes from 52 articles. The most frequently represented core area was pathophysiological manifestations, with 33 outcomes reported in 29/52 articles (56%). Death was the most frequently reported outcome. One-third of outcomes were reported by a single study. The most diversely measured outcome was cognition and intelligence/IQ for which eight unique measurement instruments were reported among 14 articles. For PKU, we identified 97 outcomes from 343 articles. The most frequently represented core area was pathophysiological manifestations with 31 outcomes reported in 281/343 articles (82%). Phenylalanine concentration was the most frequently reported outcome. Sixteen percent of outcomes were reported by a single study. Similar to MCAD deficiency, the most diversely measured PKU outcome was cognition and intelligence/IQ with 39 different instruments reported among 82 articles. CONCLUSIONS: Heterogeneity of reported outcomes and outcome measurement instruments across published studies for both MCAD deficiency and PKU highlights the need for COSs for these diseases, to promote the use of meaningful outcomes and facilitate comparisons across studies

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

The Economics of 1.5°C Climate Change

The economic case for limiting warming to 1.5°C is unclear, due to manifold uncertainties. However, it cannot be ruled out that the 1.5°C target passes a cost-benefit test. Costs are almost certainly high: The median global carbon price in 1.5°C scenarios implemented by various energy models is more than US$100 per metric ton of CO2 in 2020, for example. Benefits estimates range from much lower than this to much higher. Some of these uncertainties may reduce in the future, raising the question of how to hedge in the near term. Maintaining an option on limiting warming to 1.5°C means targeting it now. Setting off with higher emissions will make 1.5°C unattainable quickly without recourse to expensive large-scale carbon dioxide removal (CDR), or solar radiation management (SRM), which can be cheap but poses ambiguous risks society seems unwilling to take. Carbon pricing could reduce mitigation costs substantially compared with ramping up the current patchwork of regulatory instruments. Nonetheless, a mix of policies is justified and technology-specific approaches may be required. It is particularly important to step up mitigation finance to developing countries, where emissions abatement is relatively cheap

JWST reveals a possible z∼11z \sim 11 galaxy merger in triply-lensed MACS0647−-JD

MACS0647$-$JD is a triply-lensed $z\sim11$ galaxy originally discovered with the Hubble Space Telescope. Here we report new JWST imaging, which clearly resolves MACS0647$-$JD as having two components that are either merging galaxies or stellar complexes within a single galaxy. Both are very small, with stellar masses $\sim10^8\,M_\odot$ and radii $r<100\,\rm pc$. The brighter larger component "A" is intrinsically very blue ($\beta\sim-2.6$), likely due to very recent star formation and no dust, and is spatially extended with an effective radius $\sim70\,\rm pc$. The smaller component "B" appears redder ($\beta\sim-2$), likely because it is older ($100-200\,\rm Myr$) with mild dust extinction ($A_V\sim0.1\,\rm mag$), and a smaller radius $\sim20\,\rm pc$. We identify galaxies with similar colors in a high-redshift simulation, finding their star formation histories to be out of phase. With an estimated stellar mass ratio of roughly 2:1 and physical projected separation $\sim400\,\rm pc$, we may be witnessing a galaxy merger 400 million years after the Big Bang. We also identify a candidate companion galaxy C $\sim3\,{\rm kpc}$ away, likely destined to merge with galaxies A and B. The combined light from galaxies A+B is magnified by factors of $\sim$8, 5, and 2 in three lensed images JD1, 2, and 3 with F356W fluxes $\sim322$, $203$, $86\,\rm nJy$ (AB mag 25.1, 25.6, 26.6). MACS0647$-$JD is significantly brighter than other galaxies recently discovered at similar redshifts with JWST. Without magnification, it would have AB mag 27.3 ($M_{UV}=-20.4$). With a high confidence level, we obtain a photometric redshift of $z=10.6\pm0.3$ based on photometry measured in 6 NIRCam filters spanning $1-5\rm\mu m$, out to $4300\,\r{A}$ rest-frame. JWST NIRSpec observations planned for January 2023 will deliver a spectroscopic redshift and a more detailed study of the physical properties of MACS0647$-$JD.Comment: 27 pages, 14 figures, submitted to Natur

Probing of Exosites Leads to Novel Inhibitor Scaffolds of HCV NS3/4A Proteinase

Hepatitis C is a treatment-resistant disease affecting millions of people worldwide. The hepatitis C virus (HCV) genome is a single-stranded RNA molecule. After infection of the host cell, viral RNA is translated into a polyprotein that is cleaved by host and viral proteinases into functional, structural and non-structural, viral proteins. Cleavage of the polyprotein involves the viral NS3/4A proteinase, a proven drug target. HCV mutates as it replicates and, as a result, multiple emerging quasispecies become rapidly resistant to anti-virals, including NS3/4A inhibitors.To circumvent drug resistance and complement the existing anti-virals, NS3/4A inhibitors, which are additional and distinct from the FDA-approved telaprevir and boceprevir α-ketoamide inhibitors, are required. To test potential new avenues for inhibitor development, we have probed several distinct exosites of NS3/4A which are either outside of or partially overlapping with the active site groove of the proteinase. For this purpose, we employed virtual ligand screening using the 275,000 compound library of the Developmental Therapeutics Program (NCI/NIH) and the X-ray crystal structure of NS3/4A as a ligand source and a target, respectively. As a result, we identified several novel, previously uncharacterized, nanomolar range inhibitory scaffolds, which suppressed of the NS3/4A activity in vitro and replication of a sub-genomic HCV RNA replicon with a luciferase reporter in human hepatocarcinoma cells. The binding sites of these novel inhibitors do not significantly overlap with those of α-ketoamides. As a result, the most common resistant mutations, including V36M, R155K, A156T, D168A and V170A, did not considerably diminish the inhibitory potency of certain novel inhibitor scaffolds we identified.Overall, the further optimization of both the in silico strategy and software platform we developed and lead compounds we identified may lead to advances in novel anti-virals