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Search Results: 1 - 10 of 193391 matches for " David K Johnson "
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Druggable Protein Interaction Sites Are More Predisposed to Surface Pocket Formation than the Rest of the Protein Surface
David K. Johnson,John Karanicolas
PLOS Computational Biology , 2013, DOI: 10.1371/journal.pcbi.1002951
Abstract: Despite intense interest and considerable effort via high-throughput screening, there are few examples of small molecules that directly inhibit protein-protein interactions. This suggests that many protein interaction surfaces may not be intrinsically “druggable” by small molecules, and elevates in importance the few successful examples as model systems for improving our fundamental understanding of druggability. Here we describe an approach for exploring protein fluctuations enriched in conformations containing surface pockets suitable for small molecule binding. Starting from a set of seven unbound protein structures, we find that the presence of low-energy pocket-containing conformations is indeed a signature of druggable protein interaction sites and that analogous surface pockets are not formed elsewhere on the protein. We further find that ensembles of conformations generated with this biased approach structurally resemble known inhibitor-bound structures more closely than equivalent ensembles of unbiased conformations. Collectively these results suggest that “druggability” is a property encoded on a protein surface through its propensity to form pockets, and inspire a model in which the crude features of the predisposed pocket(s) restrict the range of complementary ligands; additional smaller conformational changes then respond to details of a particular ligand. We anticipate that the insights described here will prove useful in selecting protein targets for therapeutic intervention.
Effects of alkaline or liquid-ammonia treatment on crystalline cellulose: changes in crystalline structure and effects on enzymatic digestibility
Ashutosh Mittal, Rui Katahira, Michael E Himmel, David K Johnson
Biotechnology for Biofuels , 2011, DOI: 10.1186/1754-6834-4-41
Abstract: From X-ray diffractograms and nuclear magnetic resonance spectra, it was revealed that treatment with liquid ammonia produced the cellulose IIII allomorph; however, crystallinity depended on treatment conditions. Treatment at a low temperature (25°C) resulted in a less crystalline product, whereas treatment at elevated temperatures (130°C or 140°C) gave a more crystalline product. Treatment of cellulose I with aqueous sodium hydroxide (16.5 percent by weight) resulted in formation of cellulose II, but also produced a much less crystalline cellulose. The relative digestibilities of the different cellulose allomorphs were tested by exposing the treated and untreated cellulose samples to a commercial enzyme mixture (Genencor-Danisco; GC 220). The digestibility results showed that the starting cellulose I samples were the least digestible (except for corn stover cellulose, which had a high amorphous content). Treatment with sodium hydroxide produced the most digestible cellulose, followed by treatment with liquid ammonia at a low temperature. Factor analysis indicated that initial rates of digestion (up to 24 hours) were most strongly correlated with amorphous content. Correlation of allomorph type with digestibility was weak, but was strongest with cellulose conversion at later times. The cellulose IIII samples produced at higher temperatures had comparable crystallinities to the initial cellulose I samples, but achieved higher levels of cellulose conversion, at longer digestion times.Earlier studies have focused on determining which cellulose allomorph is the most digestible. In this study we have found that the chemical treatments to produce different allomorphs also changed the crystallinity of the cellulose, and this had a significant effect on the digestibility of the substrate. When determining the relative digestibilities of different cellulose allomorphs it is essential to also consider the relative crystallinities of the celluloses being tested.Cellulose is th
Anti-inflammatory effects of methoxyphenolic compounds on human airway cells
Kenneth R Houser, David K Johnson, Faoud T Ishmael
Journal of Inflammation , 2012, DOI: 10.1186/1476-9255-9-6
Abstract: Human airway cells were stimulated with TNF-α in the presence or absence of 4-substituted methoxyphenols and resveratrol. The expression of various cytokines was measured by qPCR, ELISAs, and protein arrays. Reactive oxygen species (ROS) production was measured with a reactive fluorescent probe (3',6'-diacetate-2',7'-dichlorofluorescein). Activation of NF-κB was measured by nuclear translocation and phosphorylation. Ribonuclear protein association with mRNA was assessed with a biotin-RNA affinity isolation assay.Multiple inflammatory mediators were inhibited by methoxyphenols, including: CCL2, CCL5, IL-6, IL-8, ICAM-1, MIF, CXCL1, CXCL10, and Serpin E1. IC50 values were obtained for each compound that showed significant anti-inflammatory activity: diapocynin (20.3 μM), resveratrol (42.7 μM), 2-methoxyhydroquinone (64.3 μM), apocynin (146.6 μM), and 4-amino-2-methoxyphenol (410 μM). The anti-inflammatory activity did not correlate with inhibition of reactive oxygen species production or NF-κB activation. However, methoxyphenols inhibited binding of the RNA-binding protein HuR to mRNA, indicating that they may act post-transcriptionally.Methoxyphenols demonstrate anti-inflammatory activity in human airway cells. More potent compounds that act via similar mechanisms may have therapeutic potential as novel anti-inflammatory agents.The airway epithelium plays a crucial role in the pathogenesis of asthma, chronic obstructive pulmonary disease, and other inflammatory lung diseases. By serving as a key interface between the host and environment, the airway participates in activation of innate immunity and production of cytokines and other inflammatory mediators in response to microbes, allergens, pollutants, and other inflammatory stimuli [1,2]. As such, the airway epithelium is a prime target for anti-inflammatory agents.The production of cytokines from the airway epithelium has been shown to play an important role in regulating inflammation associated with respiratory dis
Revealing the Organization of Complex Adaptive Systems through Multivariate Time Series Modeling
David G. Angeler,Stina Drakare,Richard K. Johnson
Ecology and Society , 2011, DOI: 10.5751/es-04175-160305
Abstract: Revealing the adaptive responses of ecological, social, and economic systems to a transforming biosphere is crucial for understanding system resilience and preventing collapse. However, testing the theory that underpins complex adaptive system organization (e.g., panarchy theory) is challenging. We used multivariate time series modeling to identify scale-specific system organization and, by extension, apparent resilience mechanisms. We used a 20-year time series of invertebrates and phytoplankton from 26 Swedish lakes to test the proposition that a few key-structuring environmental variables at specific scales create discontinuities in community dynamics. Cross-scale structure was manifested in two independent species groups within both communities across lakes. The first species group showed patterns of directional temporal change, which was related to environmental variables that acted at broad spatiotemporal scales (reduced sulfate deposition, North Atlantic Oscillation). The second species group showed fluctuation patterns, which often could not be explained by environmental variables. However, when significant relationships were found, species–group trends were predicted by variables (total organic carbon, nutrients) that acted at narrower spatial scales (i.e., catchment and lake). Although the sets of environmental variables that predicted the species groups differed between phytoplankton and invertebrates, the scale-specific imprints of keystone environmental variables for creating cross-scale structure were clear for both communities. Temporal trends of functional groups did not track the observed structural changes, suggesting functional stability despite structural change. Our approach allows for identifying scale-specific patterns and processes, thus providing opportunities for better characterization of complex adaptive systems organization and dynamics. This, in turn, holds potential for more accurate evaluation of resilience in disparate system types (ecological, social, economic).
Insight on Invasions and Resilience Derived from Spatiotemporal Discontinuities of Biomass at Local and Regional Scales
David G. Angeler,Craig R. Allen,Richard K. Johnson
Ecology and Society , 2012, DOI: 10.5751/es-04928-170232
Abstract: Understanding the social and ecological consequences of species invasions is complicated by nonlinearities in processes, and differences in process and structure as scale is changed. Here we use discontinuity analyses to investigate nonlinear patterns in the distribution of biomass of an invasive nuisance species that could indicate scale-specific organization. We analyze biomass patterns in the flagellate Gonyostomum semen (Raphidophyta) in 75 boreal lakes during an 11-year period (1997-2007). With simulations using a unimodal null model and cluster analysis, we identified regional groupings of lakes based on their biomass patterns. We evaluated the variability of membership of individual lakes in regional biomass groups. Temporal trends in local and regional discontinuity patterns were analyzed using regressions and correlations with environmental variables that characterize nutrient conditions, acidity status, temperature variability, and water clarity. Regionally, there was a significant increase in the number of biomass groups over time, indicative of an increased number of scales at which algal biomass organizes across lakes. This increased complexity correlated with the invasion history of G. semen and broad-scale environmental change (recovery from acidification). Locally, no consistent patterns of lake membership to regional biomass groups were observed, and correlations with environmental variables were lake specific. The increased complexity of regional biomass patterns suggests that processes that act within or between scales reinforce the presence of G. semen and its potential to develop high-biomass blooms in boreal lakes. Emergent regional patterns combined with locally stochastic dynamics suggest a bleak future for managing G. semen, and more generally why invasive species can be ecologically successful.
Hierarchical Dynamics of Ecological Communities: Do Scales of Space and Time Match?
David G. Angeler, Emma G?the, Richard K. Johnson
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0069174
Abstract: Theory posits that community dynamics organize at distinct hierarchical scales of space and time, and that the spatial and temporal patterns at each scale are commensurate. Here we use time series modeling to investigate fluctuation frequencies of species groups within invertebrate metacommunities in 26 boreal lakes over a 20-year period, and variance partitioning analysis to study whether species groups with different fluctuation patterns show spatial signals that are commensurate with the scale-specific fluctuation patterns identified. We identified two groups of invertebrates representing hierarchically organized temporal dynamics: one species group showed temporal variability at decadal scales (slow patterns of change), whilst another group showed fluctuations at 3 to 5-year intervals (faster change). This pattern was consistently found across all lakes studied. A spatial signal was evident in the slow but not faster-changing species groups. As expected, the spatial signal for the slow-changing group coincided with broad-scale spatial patterns that could be explained with historical biogeography (ecoregion delineation, and dispersal limitation assessed through a dispersal trait analysis). In addition to spatial factors, the slow-changing groups correlated with environmental variables, supporting the conjecture that boreal lakes are undergoing environmental change. Taken together our results suggest that regionally distinct sets of taxa, separated by biogeographical boundaries, responded similarly to broad-scale environmental change. Not only does our approach allow testing theory about hierarchically structured space-time patterns; more generally, it allows assessing the relative role of the ability of communities to track environmental change and dispersal constraints limiting community structure and biodiversity at macroecological scales.
Predicting costs of care in heart failure patients
Smith David H,Johnson Eric S,Blough David K,Thorp Micah L
BMC Health Services Research , 2012, DOI: 10.1186/1472-6963-12-434
Abstract: Background Identifying heart failure patients most likely to suffer poor outcomes is an essential part of delivering interventions to those most likely to benefit. We sought a comprehensive account of heart failure events and their cumulative economic burden by examining patient characteristics that predict increased cost or poor outcomes. Methods We collected electronic medical data from members of a large HMO who had a heart failure diagnosis and an echocardiogram from 1999–2004, and followed them for one year. We examined the role of demographics, clinical and laboratory findings, comorbid disease and whether the heart failure was incident, as well as mortality. We used regression methods appropriate for censored cost data. Results Of the 4,696 patients, 8% were incident. Several diseases were associated with significantly higher and economically relevant cost changes, including atrial fibrillation (15% higher), coronary artery disease (14% higher), chronic lung disease (29% higher), depression (36% higher), diabetes (38% higher) and hyperlipidemia (21% higher). Some factors were associated with costs in a counterintuitive fashion (i.e. lower costs in the presence of the factor) including age, ejection fraction and anemia. But anemia and ejection fraction were also associated with a higher death rate. Conclusions Close control of factors that are independently associated with higher cost or poor outcomes may be important for disease management. Analysis of costs in a disease like heart failure that has a high death rate underscores the need for economic methods to consider how mortality should best be considered in costing studies.
Identification of microspore-active promoters that allow targeted manipulation of gene expression at early stages of microgametogenesis in Arabidopsis
David Honys, Sung-Aeong Oh, David Reňák, Maarten Donders, Blanka ?olcová, James Johnson, Rita Boudová, David Twell
BMC Plant Biology , 2006, DOI: 10.1186/1471-2229-6-31
Abstract: Transcriptomic datasets covering four progressive stages of male gametophyte development in Arabidopsis were used to select candidate genes showing early expression profiles that were male gametophyte-specific. Promoter-GUS reporter analysis of candidate genes identified three promoters (MSP1, MSP2, and MSP3) that are active in microspores and are otherwise specific to the male gametophyte and tapetum. The MSP1 and MSP2 promoters were used to successfully complement and restore the male transmission of the gametophytic two-in-one (tio) mutant that is cytokinesis-defective at first microspore division.We demonstrate the effective application of MSP promoters as tools that can be used to elucidate gametophytic gene functions in microspores in a male-specific manner.The male gametophyte of flowering plants displays a highly reduced structure of two or three cells at maturity and its development provides an excellent system to study many fundamentally important biological processes such as cell polarity, cell division and cell fate determination (reviewed by [1]). An increasing collection of mutations and genes have been characterized that act gametophytically and have been shown to be important for post-meiotic cell division during pollen development in Arabidopsis. These include MOR1/GEM1 [2] and TIO [3], whose functions are essential for regular cell polarity and cytokinesis at first microspore division, termed pollen mitosis I. However, mutations in such essential genes cause gametophytic embryo sac defects and sporophytic lethality [2,3]. This prevents the analysis of homozygous mutations and hinders the functional analysis of their role(s) in specific cell types such as microspores. The native promoters of essential genes such as TIO are not useful tools to examine effects of mis-expression of gene or protein domains during pollen development since their broad activities in other sporophytic tissues can be detrimental to early vegetative development prior to gamet
A Platform for Supporting Micro-Collaborations in a Diverse Device Environment
David Johnson
International Journal of Interactive Mobile Technologies (iJIM) , 2009, DOI: 10.3991/ijim.v3i4.1039
Abstract: Collaborative software is usually thought of as providing audio-video conferencing services, application/desktop sharing, and access to large content repositories. However mobile device usage is characterized by users carrying out short and intermittent tasks sometimes referred to as ‘micro-tasking’. Micro-collaborations are not well supported by traditional groupware systems and the work in this paper seeks out to address this. Mico is a system that provides a set of application level peer-to-peer services for the ad-hoc formation and facilitation of collaborative groups across a diverse mobile device domain. The system builds on the Java ME bindings of the JXTA P2P protocols, and is designed with an approach to use the lowest common denominators that are required for collaboration between varying degrees of mobile device capability. To demonstrate how our platform facilitates application development, we built an exemplary set of demonstration applications and include code examples here to illustrate the ease and speed afforded when developing collaborative software with Mico.
Absence of Observed Unspeakably Large Black Holes Tells Us the Curvature of Space
David Johnson
Physics , 2015,
Abstract: Using black-hole arguments with widely accepted premises, we show that it is extremely improbable that space is Euclidean, and that it is unspeakably improbable that space is hyperbolic. Independently, using an argument which makes no appeal to black holes, but only to the ratio of volumes in hyperbolic space of Hubble volumes from different times, we prove that space is not hyperbolic. We conclude by discussing some implications of these results, when conjoined with the assumption that the entropy of a black hole is the hidden information about its internal configuration.
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