Apolipoprotein A-I (apoA-I) is the principal protein of high density lipoprotein particles (HDL). ApoA-I contains a globular N-terminal domain (residues 1-43) and a lipid-binding C-terminal domain (residues 44 -243).Here we propose a detailed model for the smallest discoidal HDL, consisting of two apoA-I molecules wrapped beltwise around a small patch of bilayer containing 160 lipid molecules. The C-terminal domain of each monomer is ringlike, a curved, planar amphipathic ␣ helix with an average of 3.67 residues per turn, and with the hydrophobic surface curved toward the lipids. We have explored all possible geometries for forming the dimer of stacked rings, subject to the hypothesis that the optimal geometry will maximize intermolecular salt bridge interactions. The resulting model is an antiparallel arrangement with an alignment matching that of the (nonplanar) crystal structure of lipid-free apoA-I. Apolipoprotein (apo)1 A-I is the major protein component of the antiatherogenic high density lipoproteins (HDL). There are eight 22-mer and two 11-mer tandem amino acid sequence repeats, each with the periodicity of an amphipathic ␣ helix (1, 2), often punctuated by prolines, encoded in exon 4 of the apoA-I gene (residues 44 -241).ApoA-I is an integral component of both spheroidal circulating HDL particles and the geometrically simpler discoidal (hockey puck-like) nascent HDL particles. The better characterized discs are small unilamellar bilayers, containing approximately 160 molecules of phospholipid, surrounded by two apoA-I monomers (3-5). Two general models have been proposed for apoA-I on the disc rim: (i) two molecules of apoA-I form a pair of continuous amphipathic ␣ helices parallel to the plane of the disc (the "double belt" model) (3, 6 -8); (ii) the 22-mer amphipathic ␣ helical repeats of apoA-I form tandem antiparallel helices perpendicular to the plane of the disc (the "picket-fence" model) (9, 10). Although total reflectance Fourier-transform infrared spectroscopy studies of discoidal HDL have been interpreted as supportive of the picket-fence model (11) because the samples were dried prior to study, these conclusions are open to question. A recent study of discoidal HDL using polarized internal reflection infrared spectroscopy under native conditions unambiguously supports the belt model (12).In the recently published x-ray structure, residues 44 -243 of apoA-I form an almost continuous amphipathic ␣ helix, and the authors suggest that these results support the double belt model for discoidal HDL (7). Because lipid has a profound effect on the conformation and orientation of protein that interacts with it (13, 14), we hypothesized that if the double belt model was correct, the geometry of a planar bilayer disc should place constraints upon lipid-associated apoA-I such that the hydrophobic face of a continuous amphipathic ␣ helix would: a) be confined to a plane and b) form the inside of a continuous amphipathic ␣ helical torus. (15) were modified to create a PITCH ϭ x option to allow unlimited var...

Our understanding of when and how humans adapted to living on the Tibetan Plateau at altitudes above 2000 to 3000 meters has been constrained by a paucity of archaeological data. Here we report data sets from the northeastern Tibetan Plateau indicating that the first villages were established only by 5200 calendar years before the present (cal yr B.P.). Using these data, we tested the hypothesis that a novel agropastoral economy facilitated year-round living at higher altitudes since 3600 cal yr B.P. This successful subsistence strategy facilitated the adaptation of farmers-herders to the challenges of global temperature decline during the late Holocene.

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Gene resequencing and association analysis present new opportunities to study the evolution of adaptive traits in crop plants. Here we apply these tools to an extensive set of barley accessions to identify a component of the molecular basis of the flowering time adaptation, a trait critical to plant survival. Using an association-based study to relate variation in flowering time to sequence-based polymorphisms in the Ppd-H1 gene, we identify a causative polymorphism (SNP48) that accounts for the observed variation in barley flowering time. This polymorphism also shows latitude-dependent geographical distribution, consistent with the expected clinal variation in phenotype with the nonresponsive form predominating in the north. Networks, genealogies, and phylogenetic trees drawn for the Ppd-H1 haplotypes reveal population structure both in wild barley and in domesticated barley landraces. The spatial distribution of these population groups indicates that phylogeographical analysis of European landraces can provide information relevant to the Neolithic spread of barley cultivation and also has implications for the origins of domesticated barley, including those with the nonresponsive ppd-H1 phenotype. Haplotypes containing the nonresponsive version of SNP48 are present in wild barley accessions, indicating that the nonresponsive phenotype of European landraces originated in wild barley. The wild accessions whose nonresponsive haplotypes are most closely similar to those of landraces are found in Iran, within a region suggested as an area for domestication of barley east of the Fertile Crescent but which has previously been thought to have contributed relatively little to the diversity of European cultivars.

Due to the great length of apolipoprotein (apo) B-100, the localization of lipid-associating domains in this protein has been difficult. To address this question, we developed a computer program called LOCATE that searches amino acid sequences to identify potential amphipathic a-helixes and /3-strands by using sets of rules for helix and strand termination. A series of model chimeric protein test datasets were created by tandem linking of amino acid sequences of multiple proteins containing four different secondary structural motifs: motif A (exchangeable plasma apolipoproteins); motif G (globular a-helical proteins); motif C (coiled-coil a-helical proteins); and motif B (0 pleated-sheet proteins). These four test datasets, as well as randomly scrambled sequences of each dataset, were analyzed by LOCATE using increasingly stringent parameters. Using intermediately stringent parameters under which significant numbers of amphipathic helixes were found only in the unscrambled motif A, two dense clusters of putative lipid-associating amphipathic helixes were located precisely in the middle and at the C-terminal end of apoB-100 (a sparse cluster of class G* helixes is located at the N-terminus). The dense clusters are located between residues 2103 through 2560 and 4061 through 4338 and have densities of 2.4 and 2.2 amphipathic helixes per 100 residues, respectively; under P lasma apolipoproteins can be grouped into two general classes, the nonexchangeable apolipoproteins (apolipoprotein [apo] B-100 and apoB-48), and the exchangeable apolipoproteins (all other apolipoproteins).1 The B apolipoproteins, present in chylomicrons, very-low-density lipoprotein, intermediate-density lipoprotein, low-density lipoprotein (LDL), and lipoprotein(a), are highly insoluble in aqueous solutions and thus remain with the lipoprotein particle throughout its metabolism.2 Because of their size and insoluble nature, it has been difficult to deduce the structural motif(s) responsible for the lipid-associating properties of the B apolipoproteins. 34 On the other

A combination of genetics and archaeology is revealing the complexity of the relationships between crop plants and their wild ancestors. Archaeobotanical studies are showing that acquisition of the full set of traits observed in domesticated cereals was a protracted process, intermediate stages being seen at early farming sites throughout the Fertile Crescent. New genetic data are confirming the multiregional nature of cereal domestication, correcting a previous view that each crop was domesticated by a rapid, unique and geographically localised process. Here we review the evidence that has prompted this reevaluation of the origins of domesticated crops in the Fertile Crescent and highlight the impact that this new multiregional model is having on modern breeding programmes.The importance of agriculture The beginning of agriculture around 10 000 years ago has repeatedly been seen as the major transition in the human past, a changeover from the natural environment in control of humans, to humans in control of the natural environment. Before agriculture, humans were hunter-gatherers, dependent on wild resources for their nutritional requirements, which led to a largely nomadic lifestyle dictated by the annual cycle of animal and plant availability. The cultivation of plants and the husbandry of animals enabled humans to exert a measure of control over their food resources, protecting them from climatic and environmental uncertainty. As a result of further stabilisation and increase in the food supply, populations grew rapidly and the need for all members of a community to devote themselves to food procurement declined, leading to stratified societies and the elaborate civilisations and world systems of the historic period. Our present-day dependence on agriculture needs no emphasis: without it the world would support only a fraction of the current human population.As such a key episode, it is no surprise that a diversity of research approaches has been applied to the study of agricultural origins. For archaeologists, agriculture is a central component in the cultural changes associated with the beginning of the Neolithic (see Glossary), with much of the recent focus on placing the domestication of plants in its correct context within the package of changes originally described by Gordon Childe as a 'revolution' [1] but now viewed as a series of distinct episodes occurring at different places at different times. Implicit in this debate has been a recognition that the transition to agriculture is itself a multi-episode process that begins with gathering from the wild and ends with the cultivation of plants that have undergone the full suite of genetic and phenotypic changes that characterise the domesticated crop [2,3]. Anthropologists, ecologists and evolutionists have proposed various models for the role of humans in this multi-episode process, these ranging from a view of agriculture as one of the inspired human inventions of the past [4] to hypotheses that define domestication as the outcome of a natural coevolu...

We have collated and reviewed published records of the genera Panicum and Setaria (Poaceae), including the domesticated millets Panicum miliaceum L. (broomcorn millet) and Setaria italica (L.) P. Beauv. (foxtail millet) in pre-5000 cal B.C. sites across the Old World. Details of these sites, which span China, centraleastern Europe including the Caucasus, Iran, Syria and Egypt, are presented with associated calibrated radiocarbon dates. Forty-one sites have records of Panicum (P. miliaceum, P. cf. miliaceum, Panicum sp., Panicum type, P. capillare (?) and P. turgidum) and 33 of Setaria (S. italica, S. viridis, S. viridis/verticillata, Setaria sp., Setaria type). We identify problems of taphonomy, identification criteria and reporting, and inference of domesticated/wild and crop/weed status of finds. Both broomcorn and foxtail millet occur in northern China prior to 5000 cal B.C.; P. miliaceum occurs contemporaneously in Europe, but its significance is unclear. Further work is needed to resolve the above issues before the status of these taxa in this period can be fully evaluated.

ApoA-I is a uniquely flexible lipid-scavenging protein capable of incorporating phospholipids into stable particles. Here we report molecular dynamics simulations on a series of progressively smaller discoidal high density lipoprotein particles produced by incremental removal of palmitoyloleoylphosphatidylcholine via four different pathways. The starting model contained 160 palmitoyloleoylphosphatidylcholines and a belt of two antiparallel amphipathic helical lipid-associating domains of apolipoprotein (apo) A-I. The results are particularly compelling. After a few nanoseconds of molecular dynamics simulation, independent of the starting particle and method of size reduction, all simulated double belts of the four lipidated apoA-I particles have helical domains that impressively approximate the x-ray crystal structure of lipid-free apoA-I, particularly between residues 88 and 186. These results provide atomic resolution models for two of the particles produced by in vitro reconstitution of nascent high density lipoprotein particles. These particles, measuring 95 angstroms and 78 angstroms by nondenaturing gradient gel electrophoresis, correspond in composition and in size/shape (by negative stain electron microscopy) to the simulated particles with molar ratios of 100:2 and 50:2, respectively. The lipids of the 100:2 particle family form minimal surfaces at their monolayer-monolayer interface, whereas the 50:2 particle family displays a lipid pocket capable of binding a dynamic range of phospholipid molecules.