Wide-Angle X-Ray Solution Scattering as a Probe of Ligand-Induced Conformational Changes in Proteins

AbstractA chemical genetics approach to functional analysis of gene products utilizes high-throughput target-based screens of compound libraries to identify ligands that modulate the activity of proteins of interest. Candidates are further screened using functional assays designed specifically for the protein—and function—of interest, suffering from the need to customize the assay to each protein. An alternative strategy is to utilize a probe to detect the structural changes that usually accompany binding of a functional ligand. Wide-angle X-ray scattering from proteins provides a means to identify a broad range of ligand-induced changes in secondary, tertiary, and quaternary structure. The speed and accuracy of data acquisition, combined with the label-free targets and binding conditions achievable, indicate that WAXS is well suited as a moderate-throughput assay in the detection and analysis of protein-ligand interactions

A community-based geological reconstruction of Antarctic Ice Sheet deglaciation since the Last Glacial Maximum

A robust understanding of Antarctic Ice Sheet deglacial history since the Last Glacial Maximum is important in order to constrain ice sheet and glacial-isostatic adjustment models, and to explore the forcing mechanisms responsible for ice sheet retreat. Such understanding can be derived from a broad range of geological and glaciological datasets and recent decades have seen an upsurge in such data gathering around the continent and Sub-Antarctic islands. Here, we report a new synthesis of those datasets, based on an accompanying series of reviews of the geological data, organised by sector. We present a series of timeslice maps for 20 ka, 15 ka, 10 ka and 5 ka, including grounding line position and ice sheet thickness changes, along with a clear assessment of levels of confidence. The reconstruction shows that the Antarctic Ice sheet did not everywhere reach the continental shelf edge at its maximum, that initial retreat was asynchronous, and that the spatial pattern of deglaciation was highly variable, particularly on the inner shelf. The deglacial reconstruction is consistent with a moderate overall excess ice volume and with a relatively small Antarctic contribution to meltwater pulse 1a. We discuss key areas of uncertainty both around the continent and by time interval, and we highlight potential priorities for future work. The synthesis is intended to be a resource for the modelling and glacial geological community

Were the Larsemann Hills ice-free through the Last Glacial Maximum?

Lake sediments in the Larsemann Hills contain a great diversity ofbiological and physical markers from which past environments can be inferred. In order to determine the timing of environmental changes it is essential to have accurate dating of sediments. We used radiometric (*loPb and I3'Cs), radiocarbon (AMS "C) and uranium series (2'*U) methods to date cores from eleven lakes. These were sampled on coastal to inland transects across the two mainpeninsulas, Broknes and Stornes, together with a single sample from the Bolingen Islands. Radiometric dating of recent sediments yielded *"Pb levels below acceptable detection limits. However, a relatively well-defined peak in I3'Cs gave a date marker which corresponds to the fallout maximum from the atmospheric testing of atomic weapons in 1964/65. Radiocarbon (AMS I4C) measurements showed stratigraphical consistency in the age-depth sequences and undisturbed laminae in some cores provides evidence that the sediments have remained undisturbed by glacial action. In addition, freshwater surface sediments were found to be in near-equilibrium with modern I4CO, and not influenced by radiocarbon contaminationprocesses. This dating program, together with geomorphological records of ice flow directions and glacial sediments, indicates that parts of Broknes were ice-free throughout the Last Glacial Maximum and that some lakes have existed continuously since at least 44 ka BP. Attempts to date sediments older than44 ka BP usingZ3*Ud ating were inconclusive. However, supporting evidence for Broknes being ice-free is provided by an Optically Stimulated Luminescence date from a glaciofluvial deposit. In contrast, Stornes only became ice-free in the mid to late Holocene. This contrasting glacial history results from the D%lk Glacier which diverts ice around Broknes. Lakes onBroknes and some offshore islands therefore contain the oldest known lacustrine sediment records from eastern Antarctica, with the area providing an ice-free oasis and refuge for plants and animals throughoutthe Last Glacial Maximum. These sediments are therefore well placed to unravel a unique lirnnological sequence of environmental and climate changes in East Antarctica from the late Pleistocene to the present. This information may help better constrain models of current climate changes and ensure the adequate protection of these lakes and their catchments from the impacts of recent human occupation

Novel Bayesian Networks for Genomic Prediction of Developmental Traits in Biomass Sorghum

The ability to connect genetic information between traits over time allow Bayesian networks to offer a powerful probabilistic framework to construct genomic prediction models. In this study, we phenotyped a diversity panel of 869 biomass sorghum (Sorghum bicolor (L.) Moench) lines, which had been genotyped with 100,435 SNP markers, for plant height (PH) with biweekly measurements from 30 to 120 days after planting (DAP) and for end-of-season dry biomass yield (DBY) in four environments. We evaluated five genomic prediction models: Bayesian network (BN), Pleiotropic Bayesian network (PBN), Dynamic Bayesian network (DBN), multi-trait GBLUP (MTr-GBLUP), and multi-time GBLUP (MTi-GBLUP) models. In fivefold cross-validation, prediction accuracies ranged from 0.46 (PBN) to 0.49 (MTr-GBLUP) for DBY and from 0.47 (DBN, DAP120) to 0.75 (MTi-GBLUP, DAP60) for PH. Forward-chaining cross-validation further improved prediction accuracies of the DBN, MTi-GBLUP and MTr-GBLUP models for PH (training slice: 30-45 DAP) by 36.4–52.4% relative to the BN and PBN models. Coincidence indices (target: biomass, secondary: PH) and a coincidence index based on lines (PH time series) showed that the ranking of lines by PH changed minimally after 45 DAP. These results suggest a two-level indirect selection method for PH at harvest (first-level target trait) and DBY (second-level target trait) could be conducted earlier in the season based on ranking of lines by PH at 45 DAP (secondary trait). With the advance of high-throughput phenotyping technologies, our proposed two-level indirect selection framework could be valuable for enhancing genetic gain per unit of time when selecting on developmental traits

Effects of stroke on medical resource use and costs in acute myocardial infarction. GUSTO I Investigators. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries Study

BACKGROUND: Stroke occurs concurrently with myocardial infarction (MI) in approximately 30 000 US patients each year. This number is expected to rise with the increasing use of thrombolytic therapy for MI. However, no data exist for the economic effect of stroke in the setting of acute MI (AMI). The purpose of this prospective study was to assess the effect of stroke on medical resource use and costs in AMI patients in the United States. METHODS AND RESULTS: Medical resource use and cost data were prospectively collected for 2566 randomly selected US GUSTO I patients (from 23 105 patients) and for the 321 US GUSTO I patients who developed non-bypass surgery-related stroke during the baseline hospitalization. Follow-up was for 1 year. All costs are expressed in 1993 US dollars. During the baseline hospitalization, stroke was associated with a reduction in cardiac procedure rates and an increase in length of stay, despite a hospital mortality rate of 37%. Together with stroke-related procedural costs of $2220 per patient, the baseline medical costs increased by 44$29 242 versus $20 301, P<0.0001). Follow-up medical costs were substantially higher for stroke survivors ($22 400 versus $5282, P<0.0001), dominated by the cost of institutional care. The main determinant for institutional care was discharge disability status. The cumulative 1-year medical costs for stroke patients were$15 092 higher than for no-stroke patients. Hemorrhagic stroke patients had a much higher hospital mortality rate than non-hemorrhagic stroke patients (53% versus 15%, P<0.001), which was associated with approximately $7200 lower mean baseline hospitali