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Search Results: 1 - 10 of 190530 matches for " G. Wesley Hatfield "
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Directed DNA Shuffling of Retrovirus and Retrotransposon Integrase Protein Domains
Xiaojie Qi, Edwin Vargas, Liza Larsen, Whitney Knapp, G. Wesley Hatfield, Richard Lathrop, Suzanne Sandmeyer
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0063957
Abstract: Chimeric proteins are used to study protein domain functions and to recombine protein domains for novel or optimal functions. We used a library of chimeric integrase proteins to study DNA integration specificity. The library was constructed using a directed shuffling method that we adapted from fusion PCR. This method easily and accurately shuffles multiple DNA gene sequences simultaneously at specific base-pair positions, such as protein domain boundaries. It produced all 27 properly-ordered combinations of the amino-terminal, catalytic core, and carboxyl-terminal domains of the integrase gene from human immunodeficiency virus, prototype foamy virus, and Saccharomyces cerevisiae retrotransposon Ty3. Retrotransposons can display dramatic position-specific integration specificity compared to retroviruses. The yeast retrotransposon Ty3 integrase interacts with RNA polymerase III transcription factors to target integration at the transcription initiation site. In vitro assays of the native and chimeric proteins showed that human immunodeficiency virus integrase was active with heterologous substrates, whereas prototype foamy virus and Ty3 integrases were not. This observation was consistent with a lower substrate specificity for human immunodeficiency virus integrase than for other retrovirus integrases. All eight chimeras containing the Ty3 integrase carboxyl-terminal domain, a candidate targeting domain, failed to target strand transfer in the presence of the targeting protein, suggesting that multiple domains of the Ty3 integrase cooperate in this function.
Predicting Positive p53 Cancer Rescue Regions Using Most Informative Positive (MIP) Active Learning
Samuel A. Danziger,Roberta Baronio,Lydia Ho,Linda Hall,Kirsty Salmon,G. Wesley Hatfield,Peter Kaiser ,Richard H. Lathrop
PLOS Computational Biology , 2009, DOI: 10.1371/journal.pcbi.1000498
Abstract: Many protein engineering problems involve finding mutations that produce proteins with a particular function. Computational active learning is an attractive approach to discover desired biological activities. Traditional active learning techniques have been optimized to iteratively improve classifier accuracy, not to quickly discover biologically significant results. We report here a novel active learning technique, Most Informative Positive (MIP), which is tailored to biological problems because it seeks novel and informative positive results. MIP active learning differs from traditional active learning methods in two ways: (1) it preferentially seeks Positive (functionally active) examples; and (2) it may be effectively extended to select gene regions suitable for high throughput combinatorial mutagenesis. We applied MIP to discover mutations in the tumor suppressor protein p53 that reactivate mutated p53 found in human cancers. This is an important biomedical goal because p53 mutants have been implicated in half of all human cancers, and restoring active p53 in tumors leads to tumor regression. MIP found Positive (cancer rescue) p53 mutants in silico using 33% fewer experiments than traditional non-MIP active learning, with only a minor decrease in classifier accuracy. Applying MIP to in vivo experimentation yielded immediate Positive results. Ten different p53 mutations found in human cancers were paired in silico with all possible single amino acid rescue mutations, from which MIP was used to select a Positive Region predicted to be enriched for p53 cancer rescue mutants. In vivo assays showed that the predicted Positive Region: (1) had significantly more (p<0.01) new strong cancer rescue mutants than control regions (Negative, and non-MIP active learning); (2) had slightly more new strong cancer rescue mutants than an Expert region selected for purely biological considerations; and (3) rescued for the first time the previously unrescuable p53 cancer mutant P152L.
Ensemble-Based Computational Approach Discriminates Functional Activity of p53 Cancer and Rescue Mutants
?zlem Demir,Roberta Baronio,Faezeh Salehi,Christopher D. Wassman,Linda Hall,G. Wesley Hatfield,Richard Chamberlin,Peter Kaiser,Richard H. Lathrop,Rommie E. Amaro
PLOS Computational Biology , 2011, DOI: 10.1371/journal.pcbi.1002238
Abstract: The tumor suppressor protein p53 can lose its function upon single-point missense mutations in the core DNA-binding domain (“cancer mutants”). Activity can be restored by second-site suppressor mutations (“rescue mutants”). This paper relates the functional activity of p53 cancer and rescue mutants to their overall molecular dynamics (MD), without focusing on local structural details. A novel global measure of protein flexibility for the p53 core DNA-binding domain, the number of clusters at a certain RMSD cutoff, was computed by clustering over 0.7 μs of explicitly solvated all-atom MD simulations. For wild-type p53 and a sample of p53 cancer or rescue mutants, the number of clusters was a good predictor of in vivo p53 functional activity in cell-based assays. This number-of-clusters (NOC) metric was strongly correlated (r2 = 0.77) with reported values of experimentally measured ΔΔG protein thermodynamic stability. Interpreting the number of clusters as a measure of protein flexibility: (i) p53 cancer mutants were more flexible than wild-type protein, (ii) second-site rescue mutations decreased the flexibility of cancer mutants, and (iii) negative controls of non-rescue second-site mutants did not. This new method reflects the overall stability of the p53 core domain and can discriminate which second-site mutations restore activity to p53 cancer mutants.
A Mathematical Model of Muscle Containing Heterogeneous Half-Sarcomeres Exhibits Residual Force Enhancement
Stuart G. Campbell,P. Chris Hatfield,Kenneth S. Campbell
PLOS Computational Biology , 2011, DOI: 10.1371/journal.pcbi.1002156
Abstract: A skeletal muscle fiber that is stimulated to contract and then stretched from L1 to L2 produces more force after the initial transient decays than if it is stimulated at L2. This behavior has been well studied experimentally, and is known as residual force enhancement. The underlying mechanism remains controversial. We hypothesized that residual force enhancement could reflect mechanical interactions between heterogeneous half-sarcomeres. To test this hypothesis, we subjected a computational model of interacting heterogeneous half-sarcomeres to the same activation and stretch protocols that produce residual force enhancement in real preparations. Following a transient period of elevated force associated with active stretching, the model predicted a slowly decaying force enhancement lasting >30 seconds after stretch. Enhancement was on the order of 13% above isometric tension at the post-stretch muscle length, which agrees well with experimental measurements. Force enhancement in the model was proportional to stretch magnitude but did not depend strongly on the velocity of stretch, also in agreement with experiments. Even small variability in the strength of half-sarcomeres (2.1% standard deviation, normally distributed) was sufficient to produce a 5% force enhancement over isometric tension. Analysis of the model suggests that heterogeneity in half-sarcomeres leads to residual force enhancement by storing strain energy introduced during active stretch in distributions of bound cross-bridges. Complex interactions between the heterogeneous half-sarcomeres then dissipate this stored energy at a rate much slower than isolated cross-bridges would cycle. Given the variations in half-sarcomere length that have been observed in real muscle preparations and the stochastic variability inherent in all biological systems, half-sarcomere heterogeneity cannot be excluded as a contributing source of residual force enhancement.
A Fast and Flexible Algorithm for the Graph-Fused Lasso
Wesley Tansey,James G. Scott
Statistics , 2015,
Abstract: We propose a new algorithm for solving the graph-fused lasso (GFL), a method for parameter estimation that operates under the assumption that the signal tends to be locally constant over a predefined graph structure. Our key insight is to decompose the graph into a set of trails which can then each be solved efficiently using techniques for the ordinary (1D) fused lasso. We leverage these trails in a proximal algorithm that alternates between closed form primal updates and fast dual trail updates. The resulting techinque is both faster than previous GFL methods and more flexible in the choice of loss function and graph structure. Furthermore, we present two algorithms for constructing trail sets and show empirically that they offer a tradeoff between preprocessing time and convergence rate.
Interaction of Carbon Dioxide Enrichment and Soil Moisture on Photosynthesis, Transpiration, and Water Use Efficiency of Soybean  [PDF]
Madegowda Madhu, Jerry L. Hatfield
Agricultural Sciences (AS) , 2014, DOI: 10.4236/as.2014.55043
Abstract:

Soybean (Glycine max (L.) Merrill) is one of the most important oil and protein sources in the world. Interactive effect of elevated carbon dioxide (CO2) and soil water availability potentially impact future food security of the world under climate change. A rhizotron growth chamber experiment was conducted to study soil moisture interactions with elevated CO2 on gaseous exchange parameters of soybean under two CO2 concentrations (380 and 800 μmol·mol-1) with three soil moisture levels. Elevated CO2 decreased photosynthetic rate (11.1% and 10.8%), stomatal conductance (40.5% and 36.0%), intercellular CO2 concentration (16.68% and 12.28%), relative intercellular CO2 concentration (17.4% and 11.2%), and transpiration rate (43.6% and 39%) at 42 and 47 DAP. This down-regulation of photosynthesis was probably caused by low leaf nitrogen content and decrease in uptake of nutrients due to decrease in stomatal conductance and transpiration rate. Water use efficiency (WUE) increased under elevated CO2 because increase in total dry weight of plant was greater than that of water use under high CO2 conditions. Plants under normal and high soil moisture levels had significantly higher photosynthetic rate (7% to 16%) favored by optimum soil moisture content and high specific water content of soybean plants. Total dry matter production was significantly high when plants grown under elevated CO2 with normal (74.3% to 137.3%) soil moisture level. Photosynthetic rate was significantly and positively correlated with leaf conductance and intercellular CO2 concentration but WUE was significantly negatively correlated with leaf conductance, intercellular CO2 concentration and transpiration rate. However, the effect of high CO2 on plants depends on availability of nutrients and soil moisture for positive feedback from CO2 enrichment.

Elevated Carbon Dioxide and Soil Moisture on Early Growth Response of Soybean  [PDF]
M. Madhu, Jerry L. Hatfield
Agricultural Sciences (AS) , 2015, DOI: 10.4236/as.2015.62027
Abstract:

Interactions between elevated [CO2] and soil water availability have the potential impact on crops and future food security of the world. The study was conducted to investigate vegetative growth response of soybeans under two [CO2] (380 and 800 μmol mol-1) with three soil moisture levels in controlled environment. Slow growth rate and altered crop phenology of soybeans were observed under elevated [CO2] at early stage (V-3/V-4), but showed positive physiologically response at later stage (R3) indicating adoptive mechanism of plants to high [CO2]. Elevated [CO2] decreases the number of leaves by 23% and 14% and reduces in leaf areas by 11.7% and 9.7% compared with ambient [CO2] at 29 and 44 days after planting (DAP), respectively. Adaptive mechanism of plants to high [CO2] produced 39% and 83.7% greater leaf number and leaf areas, respectively at later stage (R3) of the crop growth (59 DAP). There was a reduction in a specific leaf area (SLA) at 29 DAP (22.2%) but an increase at 44 DAP (1.4%) and 58 DAP (8.5%) under elevated [CO2]. Dry matter production of plants was increased significantly for elevated [CO2]. Increase in leaf C (<1%) and reduction in N concentration (6.0% - 9.5%) increased the C:N ratio of soybean leaves (4.4% - 12.98%) under elevated [CO2]. Elevated [CO2] with normal soil moisture condition produced a maximum number of pods (54.8% - 122.4%) and an increase in dry weight of pods (29.8% - 56.6%). Plants under elevated [CO2] produced significantly greater numbers of root nodules per plant by 114% compared with plants under ambient [CO2] at 44 DAP. These results show a direct and interactive effect of elevated [CO2] and soil moisture on plant growth that will affect not only the global food security but also nutritional security.

Indiscipline, or, The Condition of Comics Studies
Charles Hatfield
Transatlantica : Revue d'études Américaines , 2010,
Abstract: “The structure of the research university needs serious rethinking,” says James Chandler, in his contribution to Critical Inquiry’s 2003 symposium on “The Future of Criticism.” Calling for, à la Foucault, a historical epistemology of the academic disciplines and indeed the very concept of disciplinarity, Chandler hopes for both “a more rigorous account of what a discipline is” and the exploration of “new possibilities for interdisciplinary connection and exploration” (359). This essay will, i...
Sense data and the philosophy of mind: Russell, James, and Mach
Gary Hatfield
Principia : an International Journal of Epistemology , 2002,
Abstract: The theory of knowledge in early twentieth-century Anglo American philosophy was oriented toward phenomenally described cognition There was a healthy respect for the mind body problem, which meant that phenomena in both the mental and physical domain were taken sinuously Bertrand Russell's developing position on sense-data and momentary particulars drew upon, and ultimately became like, the neutral monism of Ernst Mach and William James Due to a more recent behaviorist and physicalist inspired "fear of the mental", this development has been down played in historical work on early analytic philosophy Such neglect as sumes that the "linguistic turn" is a proper and permanent effect of twentieth century philosophy, an assumption that distorts early analytic historiography, and begs a substantive philosophical question about thought and cognition.
Spatial variation of carbon dioxide fluxes in corn and soybean fields  [PDF]
Jerry L. Hatfield, Timothy B. Parkin
Agricultural Sciences (AS) , 2012, DOI: 10.4236/as.2012.38120
Abstract: Spatial variation of soil carbon dioxide (CO2) flux during a growing season within corn and soybean canopies has not been quantified. These cropping systems are the most intense in the United States and the potential for carbon (C) sequestration in these systems through changes in soil management practices create an opportunity for reduction in greenhouse gas emissions; however, the need to understand the variation in fields is critical to evaluating changes in management systems. A study was designed to evaluate the spatial variation in soil CO2 fluxes along two transects in corn and soybean fields. Samples were collected every 5 m along a 100 m transect between the rows of the crop and also along a transect in which the plants had been removed to reduce the potential of root respiration. Soil CO2 fluxes were collected at each position with air temperature, soil temperature at 0.05 m, and soil water content (0 - 0.06 m). At the end of the season, soil samples for the upper 0.1 m were collected for soil organic C content, pH, sand, silt, and clay contents. On each day measurements were made, the observed CO2 emissions were scaled by dividing the CO2 flux at each position by the mean CO2 flux of the entire transect. Observed CO2 fluxes were signifycantly larger in the row than in the fallow position for both crops. There were no differences between the corn and soybean fallow transects; however, the corn row samples were larger than the soybean row samples. No consistent spatial patterns were observed in the CO2 fluxes or any of the soil properties over the course of the study. When the CO2 flux data were combined over the season, there was a significant spatial pattern in the fallow transects for both crops but not for the row transects. Sampling for CO2 flux values in cropping systems has to consider the presence of a crop canopy and the amount of root respiration.
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