Direct quantification of terrestrial biosphere responses to global change is crucial for projections of future climate change in Earth system models. Here, we synthesized ecosystem carbon-cycling data from 1,119 experiments performed over the past four decades concerning changes in temperature, precipitation, CO 2 and nitrogen across major terrestrial vegetation types of the world. Most experiments manipulated single rather than multiple global change drivers in temperate ecosystems of the USA, Europe and China. The magnitudes of warming and elevated CO 2 treatments were consistent with the ranges of future projections, whereas those of precipitation changes and nitrogen inputs often exceeded the projected ranges. Increases in global change drivers consistently accelerated, but decreased precipitation slowed down carbon-cycle processes. Nonlinear (including synergistic and antagonistic) effects among global change drivers were rare. Belowground carbon allocation responded negatively to increased precipitation and nitrogen addition and positively to decreased precipitation and elevated CO 2. The sensitivities of carbon variables to multiple global change drivers depended on the background climate and ecosystem condition, suggesting that Earth system models should be evaluated using site-specific conditions for best uses of this large dataset. Together, this synthesis underscores an urgent need to explore the interactions among multiple global change drivers in underrepresented regions such as semi-arid ecosystems, forests in the tropics and subtropics, and Arctic tundra when forecasting future terrestrial carbon-climate feedback.

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ABCA4 is a member of the ABCA subfamily of ATP binding cassette (ABC) transporters that is expressed in rod and cone photoreceptors of the vertebrate retina. ABCA4, also known as the Rim protein and ABCR, is a large 2273 amino acid glycoprotein organized as two tandem halves, each containing a single membrane spanning segment followed sequentially by a large exocytoplasmic domain, a multispanning membrane domain and a nucleotide binding domain. Over 500 mutations in the gene encoding ABCA4 are associated with a spectrum of related autosomal recessive retinal degenerative diseases including Stargardt macular degeneration, cone-rod dystrophy and a subset of retinitis pigmentosa. Biochemical studies on the purified ABCA4 together with analysis of abca4 knockout mice and patients with Stargardt disease have implicated ABCA4 as a retinylidenephosphatidylethanolamine transporter that facilitates the removal of potentially reactive retinal derivatives from photoreceptors following photoexcitation. Knowledge of the genetic and molecular basis for ABCA4 related retinal degenerative diseases is being used to develop rationale therapeutic treatments for this set of disorders.

ABCA4, a member of the family of ATP binding cassette (ABC) proteins found in rod and cone photoreceptors, has been implicated in the transport of retinoid compounds across the outer segment disk membrane following the photoactivation of rhodopsin. Mutations in the ABCA4 gene are responsible for Stargardt macular dystrophy and related retinal degenerative diseases that cause a loss in vision. To identify the retinoid substrate that interacts with ABCA4, we have isolated ABCA4 from rod outer segment disk membranes on an immunoaffinity matrix and analyzed retinoid compounds that bind to ABCA4 using high performance liquid chromatography and radiolabeling methods. When all-trans-retinal was added to ABCA4 in the presence of phosphatidylethanolamine, ϳ0.9 mol of N-retinylidenephosphatidylethanolamine and 0.3 mol of all-trans-retinal were bound per mol of ABCA4 with an apparent K d of 2-5 M. ATP and GTP released these retinoids from ABCA4, whereas ADP, GDP, and nonhydrolyzable derivatives, adenosine 5-(␤,␥-imido)triphosphate and guanosine 5-(␤,␥-imido)triphosphate, were ineffective. One mole of N-retinyl-phosphatidylethanolamine, the reduced form of N-retinylidene-phosphatidylethanolamine, bound per mol of ABCA4, whereas 0.3 mol of all-trans-retinal were bound in the absence of phosphatidylethanolamine. No binding of all-trans-retinol to ABCA4 was observed. Our results indicate that ABCA4 preferentially binds N-retinylidene-phosphatidylethanolamine with high affinity in the absence of ATP. Our studies further suggest that ATP binding and hydrolysis induces a protein conformational change that causes N-retinylidene-phosphatidylethanolamine to dissociate from ABCA4.ABCA4, also known as ABCR or the rim protein, is a member of the ABCA subfamily of ATP binding cassette (ABC) 1 transporters (1-3). It is localized along the rims and incisures of rod and cone photoreceptor outer segment disk membranes where it is thought to play a role in the visual cycle (3-5). Mutations in the gene encoding ABCA4 are responsible for a variety of autosomal recessive retinal degenerative diseases that cause a severe loss in vision. These include Stargardt macular dystrophy, fundus flavimaculatus, cone-rod dystrophy, and retinitis pigmentosa (1, 6 -9). Mutations in ABCA4 have also been suggested to predispose individuals to age-related macular degeneration (10). ABCA4 is a 250-kDa glycoprotein that is organized as two tandemly arranged halves each containing a transmembrane segment followed by a large extracellular domain, a multispanning membrane domain, and a nucleotide binding domain (3, 11). Biochemical studies have implicated ABCA4 in the movement of retinoids across the disk membrane. The ATPase activity of immunoaffinity purified ABCA4 is increased up to 4-fold by the addition of 11-cis or all-trans-retinal, but not other retinoids (12)(13)(14). Abca4 knockout mice show a light-dependent increase in all-trans-retinal, N-retinylidene-PE, and PE in photoreceptor outer segments, and a progressive accumulation of the diretinal pyridinium ...