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The Shake-and-Bake method of structure determination is a new direct methods phasing algorithm based on a minimum-variance, phase invariant residual, which is referred to as the minimal principle. Previously, the algorithm had been applied only to known structures. This algorithm has now been applied to two previously unknown structures that contain 105 and 110 non-hydrogen atoms, respectively. This report focuses on (i) algorithmic and parametric optimizations of Shake-and-Bake and (ii) the determination of two previously unknown structures. Traditional tangent formula phasing techniques were unable to unravel these two new structures.

The crystal structure of triclinic lysozyme, comprised of 1,001 non-H protein atoms and ≈ 200 bound water molecules, has been determined ab initio (using native data alone) by the ``Shake-and-Bake'' method by using the computer program SnB. This is the largest structure determined so far by the SnB program. Initial experiments, using default SnB parameters derived from studies of smaller molecules, were unsuccessful. In fact, such experiments produced electron density maps dominated by a single large peak. This problem was overcome by considering the choice of protocol used during the parameter-shift phase refinement. When each phase was subjected to a single shift of ± 157.5 degrees during each SnB cycle, an unusually high percentage of random trials (≈ 22%) yielded correct solutions within 750 cycles. This success rate is higher than that typically observed, even for much smaller structures.

Deoxycorticosterone-adenine monohydrate is the first complex involving a steroid and a component of DNA to be successfully crystallized and studied by single crystal x-ray analysis. Hydrogen bonds between O(20) and N(6) as well as O(21) and N(1) connect the corticoid side chain to an adenine molecule. The molecules are also packed such that a second adenine moiety is situated over the $\\delta ^{4}$-3-one region of the steroid. These observations of the solid state suggest ways in which steroids and nucleic acids may interact in vivo.

The x-ray structure of a short-chain dehydrogenase, the bacterial holo 3α,20β-hydroxysteroid dehydrogenase (EC 1.1.1.53), is described at 2.6Å resolution. This enzyme is active as a tetramer and crystallizes with four identical subunits in the asymmetric unit. It has the α/β fold characteristic of the dinucleotide binding region. The fold of the rest of the subunit, the quarternary structure, and the nature of the cofactor-enzyme interactions are, however, significantly different from those observed in the long-chain dehydrogenases. The architecture of the postulated active site is consistent with the observed stereospecificity of the enzyme and the fact that the tetramer is the active form. There is only one cofactor and one substrate-binding site per subunit; the specificity for both 3α- and 20β-ends of the steroid results from the binding of the steroid in two orientations near the same cofactor at the same catalytic site.

Sir: There has been strongly prevalent in New-York State, and to a marked extent in the neighboring States, a very derogatory opinion of the student body of Cornell University. The general opinion is that Cornell is a \"loose\" university; that its students are as a class, free from restraint, wild, turbulent, and to a great extent, immoral and irreligious; that the classes, especially the under-classes, are continually...

Showcases the wealth of new research on sacred imagery found in 12 states and 4 Canadian provinces. In archaeology, rock-art—any long-lasting marking made on a natural surface—is similar to material culture (pottery and tools) because it provides a record of human activity and ideology at that site. Petroglyphs, pictographs, and dendroglyphs (tree carvings) have been discovered and recorded throughout the eastern woodlands of North America on boulders, bluffs, and trees, in caves and in rock shelters. These cultural remnants scattered on the landscape can tell us much about the belief systems of the inhabitants that left them behind. The Rock-Art of Eastern North America brings together 20 papers from recent research at sites in eastern North America, where humidity and the actions of weather, including acid rain, can be very damaging over time. Contributors to this volume range from professional archaeologists and art historians to avocational archaeologists, including a surgeon, a lawyer, two photographers, and an aerospace engineer. They present information, drawings, and photographs of sites ranging from the Seven Sacred Stones in Iowa to the Bald Friar Petroglyphs of Maryland and from the Lincoln Rise Site in Tennessee to the Nisula Site in Quebec. Discussions of the significance of artist gender, the relationship of rock-art to mortuary caves, and the suggestive link to the peopling of the continent are particularly notable contributions. Discussions include the history, ethnography, recording methods, dating, and analysis of the subject sites and integrate these with the known archaeological data.

Genome-wide association studies (GWASs) are a valuable tool for understanding the biology of complex human traits and diseases, but associated variants rarely point directly to causal genes. In the present study, we introduce a new method, polygenic priority score (PoPS), that learns trait-relevant gene features, such as cell-type-specific expression, to prioritize genes at GWAS loci. Using a large evaluation set of genes with fine-mapped coding variants, we show that PoPS and the closest gene individually outperform other gene prioritization methods, but observe the best overall performance by combining PoPS with orthogonal methods. Using this combined approach, we prioritize 10,642 unique gene–trait pairs across 113 complex traits and diseases with high precision, finding not only well-established gene–trait relationships but nominating new genes at unresolved loci, such as LGR4 for estimated glomerular filtration rate and CCR7 for deep vein thrombosis. Overall, we demonstrate that PoPS provides a powerful addition to the gene prioritization toolbox. Polygenic Priority Score (PoPS) prioritizes candidate effector genes at complex trait loci by integrating genome-wide association summary statistics with other data types. Combining PoPS with methods that leverage local genetic signals further improves the performance.

Genome-wide association studies (GWAS) have identified thousands of noncoding loci that are associated with human diseases and complex traits, each of which could reveal insights into the mechanisms of disease 1 . Many of the underlying causal variants may affect enhancers 2 , 3 , but we lack accurate maps of enhancers and their target genes to interpret such variants. We recently developed the activity-by-contact (ABC) model to predict which enhancers regulate which genes and validated the model using CRISPR perturbations in several cell types 4 . Here we apply this ABC model to create enhancer–gene maps in 131 human cell types and tissues, and use these maps to interpret the functions of GWAS variants. Across 72 diseases and complex traits, ABC links 5,036 GWAS signals to 2,249 unique genes, including a class of 577 genes that appear to influence multiple phenotypes through variants in enhancers that act in different cell types. In inflammatory bowel disease (IBD), causal variants are enriched in predicted enhancers by more than 20-fold in particular cell types such as dendritic cells, and ABC achieves higher precision than other regulatory methods at connecting noncoding variants to target genes. These variant-to-function maps reveal an enhancer that contains an IBD risk variant and that regulates the expression of PPIF to alter the membrane potential of mitochondria in macrophages. Our study reveals principles of genome regulation, identifies genes that affect IBD and provides a resource and generalizable strategy to connect risk variants of common diseases to their molecular and cellular functions. Mapping enhancer regulation across human cell types and tissues illuminates genome function and provides a resource to connect risk variants for common diseases to their molecular and cellular functions.

Species sensitivity to forest fragmentation varies latitudinally, peaking in the tropics. A prominent explanation for this pattern is that historical landscape disturbance at higher latitudes has removed fragmentation-sensitive species or promoted the evolution of more resilient survivors. However, it is unclear whether this so-called extinction filter is the dominant driver of geographic variation in fragmentation sensitivity, particularly because climatic factors may also cause latitudinal gradients in dispersal ability, a key trait mediating sensitivity to habitat fragmentation. Here we combine field survey data with a morphological proxy for avian dispersal ability (hand-wing index) to assess responses to forest fragmentation in 1,034 bird species worldwide. We find that fragmentation sensitivity is strongly predicted by dispersal limitation and that other factors—latitude, body mass and historical disturbance events—have relatively limited explanatory power after accounting for species differences in dispersal. We also show that variation in dispersal ability is only weakly predicted by historical disturbance and more strongly associated with intra-annual temperature fluctuations (seasonality). Our results suggest that climatic factors play a dominant role in driving global variation in the impacts of forest fragmentation, emphasizing the need for more nuanced environmental policies that take into account local context and associated species traits. Field survey data from 1,034 bird species worldwide are used to show that species’ sensitivities to habitat fragmentation are more strongly related to their dispersal ability than to latitude and past habitat disturbance, and that variation in dispersal ability is in turn strongly associated with climate.