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Inaccurate representations of iceberg calving from ice shelves are a large source of uncertainty in mass-loss projections from the Antarctic ice sheet. Here, we address this limitation by implementing and testing a continuum damage-mechanics model in a continental scale ice-sheet model. The damage-mechanics formulation, based on a linear stability analysis and subsequent long-wavelength approximation of crevasses that evolve in a viscous medium, links damage evolution to climate forcing and the large-scale stresses within an ice shelf. We incorporate this model into the BISICLES ice-sheet model and test it by applying it to idealized (1) ice tongues, for which we present analytical solutions and (2) buttressed ice-shelf geometries. Our simulations show that the model reproduces the large disparity in lengths of ice shelves with geometries and melt rates broadly similar to those of four Antarctic ice shelves: Erebus Glacier Tongue (length ~ 13 km), the unembayed portion of Drygalski Ice Tongue (~ 65 km), the Amery Ice Shelf (~ 350 km) and the Ross Ice Shelf (~ 500 km). These results demonstrate that our simple continuum model holds promise for constraining realistic ice-shelf extents in large-scale ice-sheet models in a computationally tractable manner.

Coupled ice sheet-ocean models capable of simulating moving grounding lines are just becoming available. Such models have a broad range of potential applications in studying the dynamics of marine ice sheets and tidewater glaciers, from process studies to future projections of ice mass loss and sea level rise. The Marine Ice Sheet-Ocean Model Intercomparison Project (MISOMIP) is a community effort aimed at designing and coordinating a series of model intercomparison projects (MIPs) for model evaluation in idealized setups, model verification based on observations, and future projections for key regions of the West Antarctic Ice Sheet (WAIS). Here we describe computational experiments constituting three interrelated MIPs for marine ice sheet models and regional ocean circulation models incorporating ice shelf cavities. These consist of ice sheet experiments under the Marine Ice Sheet MIP third phase (MISMIP+), ocean experiments under the Ice Shelf-Ocean MIP second phase (ISOMIP+) and coupled ice sheet-ocean experiments under the MISOMIP first phase (MISOMIP1). All three MIPs use a shared domain with idealized bedrock topography and forcing, allowing the coupled simulations (MISOMIP1) to be compared directly to the individual component simulations (MISMIP+ and ISOMIP+). The experiments, which have qualitative similarities to Pine Island Glacier Ice Shelf and the adjacent region of the Amundsen Sea, are designed to explore the effects of changes in ocean conditions, specifically the temperature at depth, on basal melting and ice dynamics. In future work, differences between model results will form the basis for the evaluation of the participating models.

CAPN5 mutations have been linked to autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV), a blinding autoimmune eye disease. Here, we link a new CAPN5 mutation to ADNIV and model the three-dimensional structure of the resulting mutant protein. In our study, a kindred with inflammatory vitreoretinopathy was evaluated by clinical eye examinations, DNA sequencing, and protein structural modeling to investigate the disease-causing mutation. Two daughters of an affected mother demonstrated symptoms of stage III ADNIV, with posterior uveitis, cystoid macular edema, intraocular fibrosis, retinal neovascularization, retinal degeneration, and cataract. The women also harbored a novel guanine to thymine (c.750G>T, p.Lys250Asn) missense mutation in exon 6 of CAPN5, a gene that encodes a calcium-activated cysteine protease, calpain-5. Modeling based on the structures of all known calpains revealed the mutation falls within a calcium-sensitive flexible gating loop that controls access to the catalytic groove. Three-dimensional modeling placed the new mutation in a region adjacent to two previously identified disease-causing mutations, all three of which likely disrupt hydrogen bonding within the gating loop, yielding a CAPN5 with altered enzymatic activity. This is the third case of a CAPN5 mutation leading to inherited uveitis and neovascular vitreoretinopathy, suggesting patients with ADNIV features should be tested for CAPN5 mutations. Structural modeling of novel variants can be used to support mechanistic consequences of the disease-causing variants.

The land ice contribution to global mean sea level rise has not yet been predicted1 using ice sheet and glacier models for the latest set of socio-economic scenarios, nor using coordinated exploration of uncertainties arising from the various computer models involved. Two recent international projects generated a large suite of projections using multiple models2,3,4,5,6,7,8, but primarily used previous-generation scenarios9 and climate models10, and could not fully explore known uncertainties. Here we estimate probability distributions for these projections under the new scenarios11,12 using statistical emulation of the ice sheet and glacier models. We find that limiting global warming to 1.5 degrees Celsius would halve the land ice contribution to twenty-first-century sea level rise, relative to current emissions pledges. The median decreases from 25 to 13 centimetres sea level equivalent (SLE) by 2100, with glaciers responsible for half the sea level contribution. The projected Antarctic contribution does not show a clear response to the emissions scenario, owing to uncertainties in the competing processes of increasing ice loss and snowfall accumulation in a warming climate. However, under risk-averse (pessimistic) assumptions, Antarctic ice loss could be five times higher, increasing the median land ice contribution to 42 centimetres SLE under current policies and pledges, with the 95th percentile projection exceeding half a metre even under 1.5 degrees Celsius warming. This would severely limit the possibility of mitigating future coastal flooding. Given this large range (between 13 centimetres SLE using the main projections under 1.5 degrees Celsius warming and 42 centimetres SLE using risk-averse projections under current pledges), adaptation planning for twenty-first-century sea level rise must account for a factor-of-three uncertainty in the land ice contribution until climate policies and the Antarctic response are further constrained.

The selective targeting of pathogenic T cells is a holy grail in the development of new therapeutics for T cell-mediated disorders, including many autoimmune diseases and graft versus host disease. We describe the development of a CD6-targeted antibody-drug conjugate (CD6-ADC) by conjugating an inactive form of monomethyl auristatin E (MMAE), a potent mitotic toxin, onto a mAb against CD6, an established T cell surface marker. Even though CD6 is present on all T cells, only the activated (pathogenic) T cells vigorously divide and thus are susceptible to the antimitotic MMAE-mediated killing via the CD6-ADC. We found CD6-ADC selectively killed activated proliferating human T cells and antigen-specific mouse T cells in vitro. Furthermore, in vivo, whereas the CD6-ADC had no significant detrimental effect on normal T cells in naive CD6-humanized mice, the same dose of CD6-ADC, but not the controls, efficiently treated 2 preclinical models of autoimmune uveitis and a model of graft versus host disease. These results provide evidence suggesting that CD6-ADC could be further developed as a potential therapeutic agent for the selective elimination of pathogenic T cells and treatment of many T cell-mediated disorders.

This randomized trial involved 160 patients with the acquired immunodeficiency syndrome (AIDS) and newly diagnosed cytomegalovirus retinitis. After four weeks, the response to induction therapy was satisfactory in 72 percent of patients who received oral valganciclovir, as compared with 77 percent of those who received intravenous ganciclovir. The median time to progression of retinitis was 160 days for the valganciclovir group and 125 days for the ganciclovir group. Cytomegalovirus retinitis remains the leading cause of visual loss in patients with the acquired immunodeficiency syndrome (AIDS). 1 – 3 Induction therapy with intravenous ganciclovir, 4 , 5 foscarnet, 5 , 6 or cidofovir, 7 , 8 followed by maintenance therapy, can effectively make cytomegalovirus retinitis inactive. If recovery of immune function is not possible, indefinite treatment is needed, and an indwelling catheter and daily intravenous medication may be required. The cost, the risk of sepsis, and the adverse effect on the quality of life associated with an indwelling catheter spurred the development of an oral formulation of ganciclovir. 9 When administered orally, ganciclovir requires three doses (up to . . .

This comparison of ranibizumab and bevacizumab to treat neovascular age-related macular degeneration showed equivalent efficacy in maintaining visual acuity. Bevacizumab was associated with more serious adverse events (mainly hospitalizations). In 2005, clinical trials established the efficacy of ranibizumab 1 , 2 (Lucentis, Genentech) for the treatment of neovascular age-related macular degeneration (AMD), the leading cause of legal blindness in the United States. While awaiting approval for ranibizumab from the Food and Drug Administration, ophthalmologists began treating neovascular AMD with off-label use of bevacizumab (Avastin, Genentech), since the drug had a target specificity similar to that of ranibizumab and was available at low cost. 3 , 4 Because the intraocular safety of bevacizumab and the duration of its therapeutic effect were unknown, the drug was usually administered only when there were signs of active . . .

Some insurance companies mandate a form of step therapy, which involves initial use of an inexpensive drug, bevacizumab, to treat diabetic macular edema. This trial compared two treatments: step therapy and use of a more expensive drug.

Macular edema is a common cause of vision loss in patients with diabetes. Chronic elevation of serum glucose levels leads to capillary damage that results in microaneurysm formation in the retina. Leakage from these microaneurysms leads to vision loss if the fluid involves the center of the fovea. The mainstay of therapy for more than 25 years was focal laser photocoagulation applied to or near the microaneurysms. 1 However, results from clinical trials of drugs that block vascular endothelial growth factor (VEGF) for the treatment of diabetic macular edema have led to a dramatic shift away from laser therapy to primary . . .

The standard upwind time evolution with a CFL-limited timestep results in spurious oscillations at the grid scale. These oscillations, which originate at the extrema, propagate throughout the computational domain and are undamped even at late times. These oscillations arise because of unphysically large fluxes leaving (entering) the maxima (minima) with the standard CFL-limited explicit methods. Regularization of the equation shows that it is diffusive at the extrema; because of this, an explicit method for the regularized equation with ... behaves fine. The paper shows that the implicit methods show stable and converging results with ...; however, surprisingly, even implicit methods are not stable with large enough timesteps. The fluid model for cosmic rays interacting with a thermal plasma (valid at space scales much larger than the cosmic ray Larmor radius) and the equation of saturated conduction in a collisionless plasma are similar to the streaming equation, so the paper's method will find applications in fluid modeling of important processes in plasma astrophysics. (ProQuest: ... denotes formulae/symbols omitted.)