Query: TETER D M

title: Iterative minimization techniques for ab initio total energy calculations: molecular dynamics and co
abstract: This article describes recent technical developments that have made the total energy pseudopotential the most powerful ab initio quantum mechanical modeling method presently available. In addition to presenting technical details of the pseudopotential method, the article aims to heighten awareness of the capabilities of the method in order to stimulate its application to as wide a range of problems in as many scientific disciplines as possible.

title: Ibuprofen Suppresses Plaque Pathology and Inflammation in a Mouse Model for Alzheimer's Disease
abstract: The brain in Alzheimer's disease (AD) shows a chronic inflammatory response characterized by activated glial cells and increased expression of cytokines and complement factors surrounding amyloid deposits. Several epidemiological studies have demonstrated a reduced risk for AD in patients using nonsteroidal anti inflammatory drugs (NSAIDs) prompting further inquiries about how NSAIDs might influence the development of AD pathology and inflammation in the CNS. We tested the impact of chronic orally administered ibuprofen, the most commonly used NSAID, in a transgenic model of AD displaying widespread microglial activation, age related amyloid deposits, and dystrophic neurites. These mice were created by overexpressing a variant of the amyloid precursor protein found in familial AD. Transgene positive (Tg+ and negative (Tg mice began receiving chow containing 375 ppm ibuprofen at 10 months of age, when amyloid plaques first appear, and were fed continuously for 6 months. This treatment produced significant reductions in final interleukin 1b and glial fibrillary acidic protein levels, as well as a significant diminution in the ultimate number and total area of b amyloid deposits. Reductions in amyloid deposition were supported by ELISA measurements showing significantly decreased SDS insoluble Ab. Ibuprofen also decreased the numbers of ubiquitin labeled dystrophic neurites and the percentage area per plaque of anti phosphotyrosine labeled microglia. Thus, the anti inflammatory drug ibuprofen, which has been associated with reduced AD risk in human epidemiological studies, can significantly delay some forms of AD pathology, including amyloid deposition, when administered early in the disease course of a transgenic mouse model of AD.

title: Genome, transcriptome, and secretome analysis of wood decay fungus Postia placenta supports unique mechanisms of lignocellulose conversion
abstract: Brown rot fungi such as Postia placenta are common inhabitants of forest ecosystems and are also largely responsible for the destructive decay of wooden structures. Rapid depolymerization of cellulose is a distinguishing feature of brown rot, but the biochemical mechanisms and underlying genetics are poorly understood. Systematic examination of the P. placenta genome, transcriptome, and secretome revealed unique extracellular enzyme systems, including an unusual repertoire of extracellular glycoside hydrolases. Genes encoding exocellobiohydrolases and cellulose binding domains, typical of cellulolytic microbes, are absent in this efficient cellulose degrading fungus. When P. placenta was grown in medium containing cellulose as sole carbon source, transcripts corresponding to many hemicellulases and to a single putative b 1 4 endoglucanase were expressed at high levels relative to glucose grown cultures. These transcript profiles were confirmed by direct identification of peptides by liquid chromatography tandem mass spectrometry (LC MS/MS) Also up regulated during growth on cellulose medium were putative iron reductases, quinone reductase, and structurally divergent oxidases potentially involved in extracellular generation of Fe(II) and H2O2. These observations are consistent with a biodegradative role for Fenton chemistry in which Fe(II) and H2O2 react to form hydroxyl radicals, highly reactive oxidants capable of depolymerizing cellulose. The P. placenta genome resources provide unparalleled opportunities for investigating such unusual mechanisms of cellulose conversion. More broadly, the genome offers insight into the diversification of lignocellulose degrading mechanisms in fungi. Comparisons with the closely related white rot fungus Phanerochaete chrysosporium support an evolutionary shift from white rot to brown rot during which the capacity for efficient depolymerization of lignin was lost.

title: Computational Alchemy: The Search for New Superhard Materials
abstract: A central challenge to modern materials science is the rational design and synthesis of new materials possessing exceptional properties. Recent advances in first principles modeling methods and the availability of increasingly powerful computational resources make this goal increasingly achievable. The strength of these modeling methods lies in their predictive ability. They are able to reproduce the crystal structures and elastic properties of a large class of materials to within 2 3% of experimental values and have predicted a number of phase transitions that have been verified experimentally. Despite the power of these methods, the process of designing materials from first principles is not usually a straight forward or simple one. It requires overcoming a number of obstacles, some of them quite formidable. First a calculable figure of merit that correlates well with the desired property must be identified. While this may be straightforward in some cases, in others such as predicting the ability of a material to isolate radionuclides over million year time scales the process of reducing complex properties to a few calculable variables can be rather difficult. Next a promising chemical system and a realistic set of crystal structures must be selected. This is not trivial because predicting the structures that can crystallize in a given system can be exceedingly challenging. However a wide variety of methods are available to aid in the generation of promising structures comparative crystallography, algorithms based upon the concepts of crystalline nets and close packing, modern alloy theory methods, and simulated annealing strategies being some examples.

title: Curcumin Structure Function, Bioavailability, and Efficacy in Models of Neuroinflammation and Alzheimer's Disease
abstract: Curcumin can reduce inflammation and neurodegeneration, but its chemical instability and metabolism raise concerns, including whether the more stable metabolite tetrahydrocurcumin (TC) may mediate efficacy. We examined the antioxidant, anti inflammatory, or anti amyloidogenic effects of dietary curcumin and TC, either administered chronically to aged Tg2576 APPsw mice or acutely to lipopolysaccharide (LPS) injected wild type mice. Despite dramatically higher drug plasma levels after TC compared with curcumin gavage, resulting brain levels of parent compounds were similar, correlating with reduction in LPS stimulated inducible nitric oxide synthase, nitrotyrosine, F2 isoprostanes, and carbonyls. In both the acute (LPS) and chronic inflammation (Tg2576) TC and curcumin similarly reduced interleukin 1b. Despite these similarities, only curcumin was effective in reducing amyloid plaque burden, insoluble b amyloid peptide (Ab) and carbonyls. TC had no impact on plaques or insoluble Ab, but both reduced Tris buffered saline soluble Ab and phospho c Jun NH2 terminal kinase (JNK) Curcumin but not TC prevented Ab aggregation. The TC metabolite was detected in brain and plasma from mice chronically fed the parent compound. These data indicate that the dienone bridge present in curcumin, but not in TC, is necessary to reduce plaque deposition and protein oxidation in an Alzheimer's model. Nevertheless, TC did reduce neuroinflammation and soluble Ab, effects that may be attributable to limiting JNK mediated transcription. Because of its favorable safety profile and the involvement of misfolded proteins, oxidative damage, and inflammation in multiple chronic degenerative diseases, these data relating curcumin dosing to the blood and tissue levels required for efficacy should help translation efforts from multiple successful preclinical models.

title: Polypeptide Flux through Bacterial Hsp70 DnaK Cooperates with Trigger Factor in Chaperoning Nascent Chains
abstract: A role for DnaK, the major E. coli Hsp70, in chaperoning de novo protein folding has remained elusive. Here we show that under nonstress conditions DnaK transiently associates with a wide variety of nascent and newly synthesized polypeptides, with a preference for chains larger than 30 kDa. Deletion of the nonessential gene encoding trigger factor, a ribosome associated chaperone, results in a doubling of the fraction of nascent polypeptides interacting with DnaK. Combined deletion of the trigger factor and DnaK genes is lethal under normal growth conditions. These findings indicate important, partially overlapping functions of DnaK and trigger factor in de novo protein folding and explain why the loss of either chaperone can be tolerated by E. coli.

title: Modeling uncertainty of expert elicitation for use in risk based optimization
abstract: Capital budgeting optimization models, used in a broad number of fields, require certain and uncertain parameters. Often times, elicited subject matter expert (SME) opinion is used as a parameter estimate, which does not always yield perfect information or correspond to a single value. Because of the uncertainty of the elicitation, the unknown true value of a parameter can be modeled as a random variable from a to be determined distribution. We estimate a univariate distribution using four different approaches, the Beta and Gaussian distributions, a standard Gaussian Kernel estimate, and an exponential epi spline. We also capture dependencies within the parameters through three multivariate approaches: the multivariate Gaussian distribution, the multivariate Kernel and the multivariate exponential epi spline. This is the first three dimensional application of the latter. Sampling from the densities, we generate scenarios and implement a superquantile risk based, capital budgeting optimization model. Numerical experiments contrast the differences between estimators, as well as their effects on an optimal solution. Our findings demonstrate that naively averaging the SME observations for use in optimization, rather than incorporating uncertainty, results in an overly optimistic portfolio. The flexibility of the exponential epi spline estimator to fuse soft information with observed data produces reasonable density functions for univariate and multivariate random variables. Including a decision maker's risk averseness through risk based optimization delivers conservative results while incorporating the uncertainty of unknown parameters. We demonstrate a 20% improvement for this specific case when using our approach as opposed to the naive method.

title: Role of p21 activated kinase pathway defects in the cognitive deficits of Alzheimer disease
abstract: Defects in dendritic spines are common to several forms of cognitive deficits, including mental retardation and Alzheimer disease. Because mutation of p21 activated kinase (PAK) can lead to mental retardation and because PAK cofilin signaling is critical in dendritic spine morphogenesis and actin dynamics, we hypothesized that the PAK pathway is involved in synaptic and cognitive deficits in Alzheimer disease. Here, we show that PAK and its activity are markedly reduced in Alzheimer disease and that this is accompanied by reduced and redistributed phosphoPAK, prominent cofilin pathology and downstream loss of the spine actin regulatory protein drebrin, which cofilin removes from actin. We found that b amyloid (Ab) was directly involved in PAK signaling deficits and drebrin loss in Ab oligomer treated hippocampal neurons and in the Appswe transgenic mouse model bearing a double mutation leading to higher Ab production. In addition, pharmacological PAK inhibition in adult mice was sufficient to cause similar cofilin pathology, drebrin loss and memory impairment, consistent with a potential causal role of PAK defects in cognitive deficits in Alzheimer disease.

title: National inventory of hospital trauma centers.
abstract: Trauma centers benefit thousands of injured individuals every day and play a critical role in responding to disasters. The last full accounting of the number and distribution of trauma centers identified 471 trauma centers in the United States in 1991.  To determine the number and configuration of trauma centers and identify gaps in coverage.  Interviews with trauma center directors (September 2001 to April 2002) data from the American Hospital Association's Annual Survey of Hospitals (2000) and the US Health Resources Administration's Area Resource File (2001) were used to determine characteristics of trauma center hospitals and the geographic areas they serve in all 50 states and in the District of Columbia. Characteristics of trauma centers were examined by level of care and compared with nontrauma centers. Hospitals are designated or certified as trauma centers by a state or regional authority or verified as trauma centers by the American College of Surgeons Committee on Trauma. Trauma centers that treat only children (n 31) were excluded.  Total number of trauma centers and number of trauma centers per million population.  In 2002, there were 1154 trauma centers in the United States, including 190 level I centers and 263 level II centers. Several states have categorized every hospital with an emergency department at some level of trauma care while others have designated a limited number of level I and level II centers only. The number of level I and II centers per million population ranges from 0.19 to 7.8 by state. When compared with nontrauma center hospitals, trauma centers are larger, more likely to be teaching hospitals, and more likely to offer specialized services.  Although the availability of trauma centers has improved, challenges remain to ensure the optimal number, distribution, and configuration of trauma centers. These challenges must be addressed, especially in light of the recent emphasis on hospital preparedness and homeland security.

title: Increased Dead Space Ventilation and Refractory Hypercapnia in Patients With Coronavirus Disease 2019: A Potential Marker of Thrombosis in the Pulmonary Vasculature
abstract: Supplemental Digital Content is available in the text.  Mortality rates in intubated coronavirus disease 2019 patients remain markedly elevated. Some patients develop sudden refractory hypercapnia and hypoxemia not explained by worsening pulmonary parenchymal disease. This case series highlights clinical findings and management of coronavirus disease 2019 patients with refractory hypercapnia despite maximal/optimal ventilatory support. Hypercapnia could not be explained by worsening lung disease or other common factors, and thus, a pulmonary vascular etiology was suggested. The pillars of management were targeted to improve pulmonary vascular patency via aggressive anticoagulation and support right ventricular function.  Four consecutive patients with confirmed coronavirus disease 2019 infection with sudden hypercapnia and hypoxemia were included.  There was sequential development of: 1) severe hypercapnia attributable to marked elevation of dead space without radiographic changes; 2) concomitant coagulopathy manifest by an increase in d dimer levels; 3) progressive shunt with consequent hypoxemia; and 4) right ventricular dysfunction. Management included extracorporeal Co2 removal, direct thrombin inhibition, pulmonary vasodilators, and inotropic support. Marked improvement in Pao2 allowed reduction in Fio2 in all patients, extracorporeal Co2 removal was discontinued in three patients over the ensuing 3 weeks, and one patient was discharged home.  We speculate that thromboinflammation with pulmonary microvasculature occlusion leads to a sudden increase in dead space and shunt resulting in severe hypercapnia and hypoxemia in coronavirus disease 2019 patients. Early identification of these physiologic and clinical biomarkers could trigger the institution of therapies aiming to reverse the hypercoagulable state and support right ventricular function.