cssi/SciSciGPT-SciSciNet huggingface dataset:
Maintenance Therapy in Advanced Non-small Cell Lung Cancer: Current Status and Future Implications

Abstract: Maintenance therapy for patients with advanced non-small cell lung cancer has been an area of intense investigation. Maintenance therapy has been divided into two broad categories: continuation maintenance when the chemotherapy or targeted agent was part of a defined number of cycles of combination therapy and in the absence of disease progression is continued as a single agent or switch maintenance when a third agent is initiated after four cycles of platinum-based double-agent chemotherapy in the absence of disease progression. Two monoclonal antibodies, cetuximab and bevacizumab, are used as continuation maintenance, but the incremental benefit of the maintenance therapy with these agents is undetermined. Phase III trials have not revealed an overall survival benefit for continuation maintenance chemotherapy, and this approach should be considered investigational. Phase III trials have demonstrated an improvement in overall survival with switch maintenance therapy with pemetrexed compared with placebo in patients with nonsquamous histology and erlotinib compared with placebo. Phase III trials have not revealed an improvement in quality of life with maintenance therapy. In the trials of maintenance therapy, 30 to 40% of patients enrolled in the observation or placebo arm did not receive second-line therapy, and among the patients who did receive second-line therapy, there was significant heterogeneity in the therapy. The development of maintenance therapy has raised issues about the role of treatment-free intervals in routine clinical care, trial design issues such as the optimal endpoint, the ethics of a placebo arm, and the implications of maintenance therapy for first-line trials.
A basic limitation of the split window method for SST retrievals when applied to a wide range of water vapor conditions

The split window method for retrieving sea surface temperatures (SST) from satellite-based observations is evaluated from radiative transfer calculations, and shown to have an inherent limitation that arises from a linear assumption in the correction scheme. This general limitation leads to significant errors (of several degrees in some cases) in the retrieved SST; the theoretical basis for the error is examined.
The Introduction and Establishment of the Alfalfa Weevil Parasite, Bathyplectes Curculionis (Thoms.), in the United States

The following article relates briefly certain features connected with the shipment to Salt Lake City, Utah, of Bathyplectes Curculionis (Thoms.), an internal parasite of the larva of the alfalfa weevil, Phytonomus posticus (Gyll.). It describes the release of the parasite in Utah, its rapid diffusion, and the various methods used since its colonization there to determine the extent of parasitism attained by it. Its previous history and its geographical distribution are considered.
A Chemical Index for Predicting Ammonium Production in Submerged Rice Soils

Nitrogen (N) deficiency limits rice production and productivity in tropical soils. The escalating cost of chemical fertilizers warrants an efficient use of external inputs of N. This can be achieved by estimating a soil's indigenous N supply. There is an urgent need for developing simple, rapid and effective methods of assessing N supplying capacity of soils. Ammonium production is the key process in the N nutrition of wetland rice because N mineralization halts at ammonium production in submerged soils. Previous work showed that organic matter and reducible iron control ammonium production in submerged soils. In this paper results are presented for 15 diverse West African rice soils, which show that regression equation connecting organic carbon (C) and reducible iron (extracted by EDTA or ammonium oxalate) with ammonium released under waterlogged condition, can be used for predicting ammonium production in these soils. Soils with higher N supplying capacity had relatively higher contents of organic C and...
The effect of audit and feedback on immunization delivery: a systematic review.

Abstract Objective: To assess the effective of audit and feedback (AF 44 were fully reviewed and 15 met eligibility criteria. Five were randomized trials. Twelve of the fifteen studies found that A&F, alone or in combination with other interventions, were associated with improvements in immunization rates. The magnitude of the effect varied from −17% to +49% change. Study design heterogeneity precluded statistical pooling of study results. Conclusions: The evidence available from published studies suggests that A&F alone may be an effective strategy for improving immunization rates. The number of well-conducted studies is small, and the effect is variable. Additional well-designed studies are needed to identify the independent effects of A&F, optimal format and frequency of A&F, and to examine its long-term effect on provider immunization practices and costs.
Quantitative Studies of the Rho(D) Antigenic Determinants on Gorilla Erythrocytes

Human and simian red blood cells were tested for 125I anti-D binding at equilibrium and for their ability to adsorb 125I anti-D. On the basis of the equilibrium quantity of red blood cell-bound anti-D at different ionic strengths, the rate of binding of anti-D, and adsorption studies, evidence has been obtained that D-antigenic specificities occur on the erythrocytes of orangutans (Pongo pygmaeus), chimpanzees (Pan troglocytes) and gorillas (Gorilla gorilla). Gorillas, like chimpanzees, appear to be polymorphic with respect to the presence of D-components on their erythrocytes. Individual animals have been found whose red blood cells take up very little anti-D and are similar to human D-negative cells. The quantity of anti-D bound at equilibrium, as a fraction of that bound to human D-positive red blood cells was: for gorillas 0.6 to 4.0; for chimpanzees 0.08 to 0.51; for orangutans 0.06 to 0.09, and for human Du red blood cells 0.04. At low ionic strength there was almost a twofold increase in anti-D binding. At low ionic strength, the adsorbing capacities of these erythrocytes, as compared to a human D-positive cell, were: orangutans 10 to 20 per cent; chimpanzees about 50 per cent; human Du 86 per cent; and gorillas 97 per cent. Evidence is presented to indicate that the discrepancy between adsorbing capacity and the binding of anti-D at equilibrium, for Du and simian erythrocytes, is due to absence of some of the D-antigenic components found on human D-positive red blood cells.
Report to Arizona-Nevada Academy of Science on the Project: Vascular Flora of Isla Tiburón and Satellite Islands, Gulf of California, Mexico

To the Board of Governors of the Arizona Nevada Academy of Science (ANAS), I am pleased to report considerable success thus far on my floris tic project focused on Isla Tibur?n and its satellite islands (Islas San Esteban, D?til, Cholludo, Alcatraz, and Patos) in the Gulf of California, Mexico. This work represents a collaborative effort between myself; Dr. Richard Feiger, Executive Director of Drylands Institute; Humerto Romero, Comc?ac (Seri people) collaborator; and Jss?s Sanch?z-Escalante, Curator of the University of Sonora Herbarium (USON). Additional Assistance has been received from Dr. Betsy Arnold, my project advisor who is an ANAS member. The project commenced in August of 2005 and since receiving funding from ANAS, December 15,2005, I have completed four field expeditions to the study area and developed a working relationship with Humberto Romero. I have collected >200 signifi cant plant specimens from the islands, representing 130 different species (Appendix 1). I presented the project to an international audience at the Fifth International Symposium on the Native Flora of Arid Lands in Hermosillo, Mexico, 29-31 March 2006.1 have completed searching the University of Arizona Herbarium (ARIZ) for voucher specimens from the islands, and have initiated work on several publications. All of the field work on the islands is being carried out under Mexican federal collecting permits, with specimens collected being deposited at ARIZ, with duplicates to the Herbario de la Universidad de Sonora (USON), the San Diego Natural History Museum Herbarium (SD), and other appropriate institutions in Mexico and the US. The goal of the project is to produce a compre hensive treatment of the flora of Isla Tibur?n and its
Effect of Ca ++ on triphosphoinositide extraction in fusing myoblasts

Ca++-dependent degradation of triphosphoinositide has been postulated to regulate levels of membrane-bound Ca++ and to generate a 1,2-diacylglycerol fusogen in cell fusion. Triphosphoinositide metabolism was therefore studied during Ca++-induced fusion of cultured chick embryo myoblasts. Using a frequently cited extraction procedure, it was found that apparent Ca++-dependent triphosphoinositide degradation was actually due to inhibition of extraction. A new procedure using the ion-pairing reagent tetrabutylammonium sulfate was developed which was unaffected by Ca++ and gave 2- to 20-fold greater extraction of triphosphoinositide than existing procedures. With this procedure, no changes in triphosphoinositide metabolism were found during myoblast fusion.
STABILITY ANALYSIS OF BORING BARS WITH ASYMMETRY

Stability analysis in machining systems is often based on linearized models of the cutting forces, and it is common to assume that chatter is due primarily to relative tool/workpiece motion normal to the workpiece surface. Reasonable agreement between theory and experiment has been noted in previous studies using these types of cutting force models, combined with machine tool structural models. In Parker's work,[[1]] a boring bar was used which had dissimilar stiffnesses in the directions tangent and normal to the workpiece surface. While good agreement between theory and experiment was found for many spindle speeds, poor agreement was noted for certain speed ranges. In these speed ranges, the relative tool/workpiece motion was primarily tangential to the workpiece surface. It has been assumed by Parker, and others, that additional terms may be required in the cutting force model to account for the tangential motion effect and to accurately predict chatter in some boring operations. This paper presents an...
Attack on Sebé, Domingo-Ferrer and Herrera-Joancomarti fingerprinting schemes

Sebe and Domingo-Ferrer proposed in a recent Letter a fingerprinting scheme that exploits the properties of dual binary Hamming codes to reduce the length of fingerprints. The authors show that this scheme is subject to an attack in which a collusion of (any) three buyers can frame an innocent buyer.
Zoopolis: A Political Theory of Animal Rights

Sue Donaldson and Will Kymlicka assert that animal advocacy has hit “roadblocks to progressive change” (1) due to inadequate “moral frameworks: a ‘welfarist’ approach, an ‘ecological’ approach, and...
Quantitative Classification of Eyes with and without Intermediate Age-related Macular Degeneration Using Optical Coherence Tomography

Objective To define quantitative indicators for the presence of intermediate age-related macular degeneration (AMD) via spectral-domain optical coherence tomography (SD-OCT) imaging of older adults. Design Evaluation of diagnostic test and technology. Participants and Controls One eye from 115 elderly subjects without AMD and 269 subjects with intermediate AMD from the Age-Related Eye Disease Study 2 (AREDS2) Ancillary SD-OCT Study. Methods We semiautomatically delineated the retinal pigment epithelium (RPE) and RPE drusen complex (RPEDC, the axial distance from the apex of the drusen and RPE layer to Bruch's membrane) and total retina (TR, the axial distance between the inner limiting and Bruch's membranes) boundaries. We registered and averaged the thickness maps from control subjects to generate a map of "normal" non-AMD thickness. We considered RPEDC thicknesses larger or smaller than 3 standard deviations from the mean as abnormal, indicating drusen or geographic atrophy (GA), respectively. We measured TR volumes, RPEDC volumes, and abnormal RPEDC thickening and thinning volumes for each subject. By using different combinations of these 4 disease indicators, we designed 5 automated classifiers for the presence of AMD on the basis of the generalized linear model regression framework. We trained and evaluated the performance of these classifiers using the leave-one-out method. Main Outcome Measures The range and topographic distribution of the RPEDC and TR thicknesses in a 5-mm diameter cylinder centered at the fovea. Results The most efficient method for separating AMD and control eyes required all 4 disease indicators. The area under the curve (AUC) of the receiver operating characteristic (ROC) for this classifier was >0.99. Overall neurosensory retinal thickening in eyes with AMD versus control eyes in our study contrasts with previous smaller studies. Conclusions We identified and validated efficient biometrics to distinguish AMD from normal eyes by analyzing the topographic distribution of normal and abnormal RPEDC thicknesses across a large atlas of eyes. We created an online atlas to share the 38 400 SD-OCT images in this study, their corresponding segmentations, and quantitative measurements.
Effect of a free radical scavenger on cadaver lung transplantation.

Abstract The pulmonary donor pool would increase substantially if lungs could be safely transplanted after cessation of circulation. To determine whether the addition of the free radical scavenger dimethylthiourea to the perfusate of cadaver lungs could improve graft function, canine donors were sacrificed, and lungs retrieved 2 hours after death. In a blinded fashion, dimethylthiourea was added to the modified Euro-Collins solution and infused into recipients (n = 9) perioperatively; a placebo was included in the perfusate of control animals (n = 9). Donor animals were ventilated with 100% oxygen only during flush and harvest. Recipients were rendered dependent upon the single left transplanted lung by occlusion of the right pulmonary artery and bronchus 1 hour after transplantation. Ventilation was maintained at a constant inspiratory oxygen fraction of 0.4. Recipients were followed up for 3 hours or until death. Three of 9 control animals survived the 8-hour observation period, whereas 6 of 9 recipients of cadaver lungs harvested with dimethylthiourea survived the observation period. Two deaths in the dimethylthiourea group occurred after 7 hours, implying that the effects of the ischemia and reperfusion injury were ameliorated by the use of this agent in this model. This study supports the notion that perfusate modification may improve the yield of cadaver lung retrieval and may allow for transplantation of lungs harvested from cadavers after cessation of circulation.
Reflective inquiry: enabling group self-regulation in inquiry-based science using the progress portfolio tool

This paper discusses how an inquiry-support software, the Progress Portfolio, can help students engage in reflective inquiry. We argue that self-regulation is one of the most critical components of reflective inquiry and present an empirical case of how the Progress Portfolio tool was designed to enable students to become self-regulated in their learning. Even though there is a rich literature on self-regulation, little has been written about group self-regulation in inquiry-based science. Preliminary results from a study with middle school students show that students do use the Progress Portfolio tool to engage in self-regulating cognitive activities, such as setting goals, planning, and monitoring their work.
Predissociation in the chemiluminescent emission spectrum of OH

Abstract Chemiluminescent emission from OH has been studied in low pressure diffusion flames of potassium vapor with haloforms, with small additions of oxygen. The OH is predissociated. The findings indicate that the 2 Σ + state of OH is probably crossed by a repulsive state with which it interacts sufficiently strongly to make possible a predissociation of the rotational kind from an attractive state with a potential maximum. The crossing occurs very close to v ′ = 2, J = 0. The f 1 spin levels of the 2 Σ + state are affected more strongly than the f 2 levels, as observed by Gaydon and Wolfhard. The state causing the predissociation may be 2 Σ − or 4 Π; we are unable to make a choice. Tunneling appears to make some contribution to the predissociation behavior.
Adsorption and Release of siRNA from Porous Silica

Porous silica particles are potential transfection agents for nucleic acid-based therapies because of their large specific surface areas and pore volumes and the ease with which they can be chemically modified to maximize the loading of cargo and to effect targeting in vivo. Here, we present a systematic study of the effects of pore size and pore modification on the adsorption and release of short, interfering RNA (siRNA) from a mesoporous silica particle developed in our laboratory. Using adsorption isotherms and release experiments, we found that the short polyamine diethylenetriamine was the best chemical modification for achieving both the adsorption and release of large amounts of siRNA. The degree of functionalization with diethylenetriamine caused drastic changes in the loading capacity and binding strength of siRNA to silica with relatively large pores (8 nm and larger), but the degree of functionalization had a weaker effect in narrow pores (4 nm). Multilayer adsorption could occur in materials with large pores (15 nm). Release experiments showed that intermediate pore sizes and intermediate degrees of functionalization resulted in the best compromise between maximizing loading (from strong adsorption) and maximizing release. Capillary electrophoresis and quantitative, real-time PCR demonstrated that siRNA was released intact and that these particles functioned as a transfection agent of mammalian cells in vitro.
Structural equivalence of individuals in social networks

The aim of this paper is to understand the interrelations among relations within concrete social groups. Social structure is sought, not ideal types, although the latter are relevant to interrelations among relations. From a detailed social network, patterns of global relations can be extracted, within which classes of equivalently positioned individuals are delineated. The global patterns are derived algebraically through a ‘functorial’ mapping of the original pattern. Such a mapping (essentially a generalized homomorphism) allows systematically for concatenation of effects through the network. The notion of functorial mapping is of central importance in the ‘theory of categories,’ a branch of modern algebra with numerous applications to algebra, topology, logic. The paper contains analyses of two social networks, exemplifying this approach.
Othello s Handkerchief: “The Recognizance and Pledge of Love”

So much ado, so much stress, so much passion and repetition about an Handkerchief! Why was not this call'd the Tragedy of the Handkerchief?… Had it been Desdemona's Garter, the Sagacious Moor might have smelt a Rat: but the Handkerchief is so remote a trifle, no Booby, on this side Mauritania, cou'd make any consequence from it. —Thomas Rymer1
On a simple deadlock recovery problem

Abstract In this note a polynomial time algorithm is given for the minimum cost recovery from a deadlock situation resulting from a new request by a single task in a deadlock free system of tasks. We obtain the algorithm by reducing this deadlock recovery problem to a particular network flow problem.
Sodium and calcium mechanisms of rhythmic bursting in excitatory neural networks of the pre-Bötzinger complex: a computational modelling study.

The neural mechanisms generating rhythmic bursting activity in the mammalian brainstem, particularly in the pre-Botzinger complex (pre-BotC), which is involved in respiratory rhythm generation, and in the spinal cord (e.g. locomotor rhythmic activity) that persist after blockade of synaptic inhibition remain poorly understood. Experimental studies in rodent medullary slices containing the pre-BotC identified two mechanisms that could potentially contribute to the generation of rhythmic bursting: one based on the persistent Na+ current (INaP), and the other involving the voltage-gated Ca2+ current (ICa) and the Ca2+-activated nonspecific cation current (ICAN), activated by intracellular Ca2+ accumulated from extracellular and intracellular sources. However, the involvement and relative roles of these mechanisms in rhythmic bursting are still under debate. In this theoretical/modelling study, we investigated Na+-dependent and Ca2+-dependent bursting generated in single cells and heterogeneous populations of synaptically interconnected excitatory neurons with INaP and ICa randomly distributed within populations. We analysed the possible roles of network connections, ionotropic and metabotropic synaptic mechanisms, intracellular Ca2+ release, and the Na+/K+ pump in rhythmic bursting generated under different conditions. We show that a heterogeneous population of excitatory neurons can operate in different oscillatory regimes with bursting dependent on INaP and/or ICAN, or independent of both. We demonstrate that the operating bursting mechanism may depend on neuronal excitation, synaptic interactions within the network, and the relative expression of particular ionic currents. The existence of multiple oscillatory regimes and their state dependence demonstrated in our models may explain different rhythmic activities observed in the pre-BotC and other brainstem/spinal cord circuits under different experimental conditions.
Titration vs. Tradition

The way titration curves are traditionally taught in the undergraduate curriculum is reviewed, and a more rational approach is advocated. A spreadsheet is then used to illustrate the various properties of titration curves and to fit titration data.
Dynamics of a dense laboratory plasma jet investigated using soft x-ray laser interferometry.

The formation and evolution of a collisional aluminum plasma jet created by optical laser irradiation of triangular grooves with pulses of $120\phantom{\rule{0.3em}{0ex}}\mathrm{ps}$ duration at an intensity of $1\ifmmode\times\else\texttimes\fi{}{10}^{12}\phantom{\rule{0.3em}{0ex}}\mathrm{W}\phantom{\rule{0.2em}{0ex}}{\mathrm{cm}}^{\ensuremath{-}2}$ were studied with experiments and simulations. Series of high-contrast soft x-ray laser interferograms obtained with a $46.9\phantom{\rule{0.3em}{0ex}}\mathrm{nm}$ laser mapped the plasma density evolution of an initially narrow plasma jet that expands along the symmetry plane and evolves into a broader plasma plume with significant side lobes. Two-dimensional simulations performed using the radiation hydrodynamic code HYDRA reveal that the jet formation is initiated by accelerated material ablated from the vertex and is augmented by the continual sequential arrival of wall material along the symmetry plane, where it collides and is redirected outward. Radiative cooling is identified as an important process in maintaining the collimation of the jet. These results demonstrate that well collimated collisional plasma jets with parameters in a range of interest can be generated with low-energy laser pulses $(l1\phantom{\rule{0.3em}{0ex}}\mathrm{J})$, opening the possibility of studying relevant plasma phenomena in a small laboratory setting.
A case study for reactor network synthesis: The vinyl chloride process

Abstract A key objective of the integrated reactor network synthesis approach is the development of waste minimizing process flowsheets ( Lakshmanan & Biegler, 1995 ). With increasing environmental concerns in process design, there is a particularly strong need to maximize conversion to product and avoid generation of wasteful byproducts within the reactor network. This also avoids expensive treatment and separation costs downstream in the process. In this study, we present an application of the mixed integer nonlinear programming (MINLP)-based reactor network synthesis strategy developed by Lakshmanan and Biegler (1996a) . Here we focus on applying these reactor network synthesis concepts to the vinyl chloride monomer production process. Vinyl chloride is currently produced by a balanced production process from ethylene, chlorine and oxygen with three separate reaction sections: oxychlorination of ethylene; direct chlorination of ethylene; and pyrolysis of ethylene dichloride. The hydrogen chloride produced in the pyrolysis reactor is used completely in the oxychlorination reactor. Byproducts such as chlorinated hydrocarbons and carbon oxides are generated by these reaction sections. These are studied using reaction kinetic models for the three reaction sections. The case study results in optimal reactor networks that improve the conversion of ethylene to vinyl chloride and minimize the formation of byproducts. These results are used to generate an improved flowsheet for the production of vinyl chloride monomer. Moreover, an overall profit maximization, that includes the effect of heat integration, is presented and a set of recommendations that improve the selectivity of vinyl chloride production are outlined. Finally, the optimal reactor structures, overall conversion and annual profit are shown to be only mildly sensitive with respect to small changes in the kinetic parameters.
Targeting device therapy: genomics of sudden death.

Sudden cardiac death (SCD), which is usually defined as death from cardiac causes within an hour of symptom onset, affects more than 3 million people annually worldwide.1 In the United States, estimates of annual sudden deaths range from 200,000 to 450,000, but are typically cited as accounting for 300,000 annually.2 With an estimated population of 300 million people in the United States, approximately 1/1,000 will die suddenly each year. Clinical factors used to predict sudden death include a prior history of aborted sudden death, left ventricular dysfunction, and the diagnosis of inherited syndromes associated with arrhythmias such as hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, long QT syndrome, and Brugada syndrome.3, 4 Diagnostic studies such as programmed electrical stimulation and T-wave alternans have proved disappointing, and the majority of SCD occurs in people without overt risk factors.5 Pharmacological therapy, with the exception of β-adrenergic blockade, does not prevent SCD.6 Implantable cardioverter defibrillators (ICDs) are effective therapy for those at risk for SCD, but their use is associated with complications during implantation, device and lead failure, inappropriate shocks, limitations to quality of life, and cost.7 In addition, when used as primary prevention for SCD in cardiomyopathy, as many as 10 ICDs must be placed to prevent one sudden death. Our laboratory and others are searching for novel biomarkers to identify heart failure patients at highest risk for sudden death.8 In this chapter, we will discuss the development and use of genomic predictors to define the population at risk for sudden cardiac death.
Focused-image holography as a dense-spray diagnostic.

The denser regions of sprays need to be probed for us to understand further the basic phenomena of the breakup of a bulk liquid into droplets and the subsequent drop dynamics. The instruments currently available to spray diagnosticians, the Malvern spray analyzer and the phase/Doppler particle analyzer, cannot be used in the denser regions of the spray and in regions where ligaments or nonspherical droplets exist. Holography, as applied in the past, has permitted the interrogation of nonspherical drops but in general has been applied to droplet-dominated dilute regions of sprays. Using a focused-image holographic system, with the advantages of an imaging lens and side lighting, we can probe highly complex regions of sprays, such as those that include bubble explosions and complex ligament formation at the nozzle exit. In this paper we present components of a focused-image holographic system for spray analysis, advantages and limitations of that system, and how the longitudinal magnification varies as a function of the length of the object along the optical path.
Intuitive ECO synthesis for high performance circuits

In the IC industry, chip design cycles are becoming more compressed, while designs themselves are growing in complexity. These trends necessitate efficient methods to handle late-stage engineering change orders (ECOs) to the functional specification, often in response to errors discovered after much of the implementation is finished. Past ECO synthesis algorithms have typically treated ECOs as functional errors and applied error diagnosis techniques to solve them. However, error diagnosis methods are primarily geared towards finding a single change, and moreover, tend to be computationally complex. In this paper, we propose a unique methodology that can systematically incorporate human intuition into the ECO process. Our methodology involves finding a set of directly substitutable points known as functional correspondences between the original implementation and the new specification by using name-preserving synthesis and user hints, to diminish the size of the ECO problem. On average, our approach can reduce the size of logic changes by 94% from those reported in current literature. We then incorporate our logic ECO changes into an incremental physical synthesis flow to demonstrate its usability in an industrial setting. Our ECO synthesis methodology is evaluated on high-performance industrial designs. Results indicate that post-ECO worst negative slack (WNS) improved 14% and total negative slack (TNS) improved 46% over pre-ECO.
On the shear strength of geophysical scale ice rubble

Abstract In many geophysical granular flows, particle angularity is an important component of the system's strength or resistance to deformation. In this work a two-dimensional particle simulation is developed for modeling systems of irregular polygonal particles. A series of numerical experiments is performed with a simulated two-dimensional shearbox filled with blocks which have a length to thickness distribution characteristic of pressure ridges.
Evolution of an open‐access quantitative bioanalytical mass spectrometry service in a drug discovery environment

Increased demand for assays for compounds at the early stages of drug discovery within the pharmaceutical industry has led to the need for open-access mass spectrometry systems for performing quantitative analysis in a variety of biological matrices. The open-access mass spectrometers described here are LC/MS/MS systems operated in 'multiple reaction monitoring' (MRM) mode to obtain the sensitivity and specificity required to quantitate low levels of pharmaceutical compounds in an excess of biological matrix. Instigation of these open-access systems has resulted in mass spectrometers becoming the detectors of choice for non-expert users, drastically reducing analytical method development time and allowing drug discovery scientists to concentrate on their core expertise of pharmacokinetics and drug metabolism. Setting up an open-access facility that effectively allows a user with minimal mass spectral knowledge to exploit the MS/MS capability of triple quadrupole mass spectrometers presents a significantly different challenge from setting up qualitative single stage mass spectrometry systems. Evolution of quantitative open access mass spectrometry within a pharmaceutical drug metabolism and pharmacokinetics group, from its beginnings as a single generic system to a series of specialist fully integrated walk-up facilities, is described.
Partitioning of Cu in estuarine waters, I. Partitioning in a poisoned system

Abstract The importance of dissolved hydrophobic organic matter in controlling the partitioning of Cu between the dissolved and particulate phases in natural waters was determined. Estuarine particulate matter was suspended in two solutions: (1) filtered seawater, and (2) filtered seawater in which the hydrophobic organic matter had been removed. Radioactive Cu was then added to each suspension. The removal of hydrophobic dissolved organic matter resulted in a two-fold increase in the distribution coefficient ( K D ) of added radioactive Cu (from 10 4.50 to 10 4.81 1/kg). The partitioning of 64 Cu in the suspensions was controlled by chemical processes dominated by complexation with particulate and dissolved organic matter.
Self frequency-locking of dye laser emission to the center of an intracavity atomic absorption frequency

Abstract We have developed a new technique for self frequency-locking laser radiation to the center of an intracavity resonant absorption frequency. Using this technique we have observed self frequency-locking of dye laser emission to the absorption frequencies of an intracavity sodium vapor. Both single and multiple-frequency locking have been observed.
Update in HIV Care

This update in the care of individuals with HIV reviews key research publications from the past year relevant to General Internal Medicine practitioners. Specific topics that we have covered include new developments in the understanding of HIV transmission, risk behavior among injection drug users, baseline resistance testing, choice of initial treatment regimens, and controversies in treatment interruption. Our selection process was based on MEDLINE review of key journals by all authors and recommendations of experts in this field. The original MEDLINE review encompassed January 1, 2005 to March 1, 2006 and has been updated to Sepetember 1, 2006. Key phrases used in the search included “HIV,” “AIDS,” “heterosexuality,” “antiretroviral treatment (ART)/highly active antiretroviral therapy (HAART),” “drug resistance,” and “risk behaviors”.
COOLING AND DETECTABILITY OF NEUTRON STARS

Surface properties, temperature effects, cooling behavior, and observability of neutron stars have been studied. For this purpose, the opacity of the surface layers is calculated both for a pure ir...
Apolipoprotein A-I attenuates palmitate-mediated NF-κB activation by reducing Toll-like receptor-4 recruitment into lipid rafts.

While high-density lipoprotein (HDL) is known to protect against a wide range of inflammatory stimuli, its anti-inflammatory mechanisms are not well understood. Furthermore, HDL's protective effects against saturated dietary fats have not been previously described. In this study, we used endothelial cells to demonstrate that while palmitic acid activates NF-κB signaling, apolipoprotein A–I, (apoA-I), the major protein component of HDL, attenuates palmitate-induced NF-κB activation. Further, vascular NF-κB signaling (IL-6, MCP-1, TNF-α) and macrophage markers (CD68, CD11c) induced by 24 weeks of a diabetogenic diet containing cholesterol (DDC) is reduced in human apoA-I overexpressing transgenic C57BL/6 mice compared to age-matched WT controls. Moreover, WT mice on DDC compared to a chow diet display increased gene expression of lipid raft markers such as Caveolin-1 and Flotillin-1, and inflammatory Toll-like receptors (TLRs) (TLR2, TLR4) in the vasculature. However apoA-I transgenic mice on DDC show markedly reduced expression of these genes. Finally, we show that in endothelial cells TLR4 is recruited into lipid rafts in response to palmitate, and that apoA-I prevents palmitate-induced TLR4 trafficking into lipid rafts, thereby blocking NF-κB activation. Thus, apoA-I overexpression might be a useful therapeutic tool against vascular inflammation.
Probing the Activator and Hydrophobic Substrate Binding Sites of PTEN by 31P NMR

PTEN (Phosphatase and Tensin Homolog) antagonizes the PI3K signaling pathway by dephosphorylating PI(3,4,5)P3 at the inositol C-3, thus suppressing cell proliferation. PI(4,5)P2, the product of dephosphorylation, activates this enzyme, possibly by binding to the N terminal region of PTEN (not visible in the crystal structure). A distinct hydrophobic pocket near the active site has also been identified (by MD simulations). We have used 31P NMR as a probe of the spatial location and functional role of these potential phospholipid binding sites. At 242.7 MHz, the linewidths of phosphodiester resonances of phosphoinositides that bind exclusively to the active site (PI, PI(4)P) are broadened consistent with intermediate exchange. Estimated linewidths for the bound activator PI(4,5)P2 are smaller. Other amphiphiles can also be affected by PTEN in a specific fashion, for example, diC7PC which is used as a matrix in assays. This ligand is likely to bind in the hydrophobic pocket identified by simulations. 31P high resolution field cycling NMR, with PTEN spin-labeled on the active site cysteine, was used to determine the distance between the unpaired electron and the phosphorus nuclei of the different bound lipids. Results of these relaxation studies indicate there are discrete sites for both substrate and activator lipids that are also separate from the region occupied by nonspecific lipids such as diC7PC (or a nonionic detergent such as Triton X-100). The distances derived are used to propose a model of PTEN regulation by the activator and matrix lipids.
Disability Among Older American Indians and Alaska Natives: An Analysis of the 2000 Census Public Use Microdata Sample

The scant literature on disabilities among American Indians and Alaska Natives (AI/ANs) suggests that this understudied minority suffers some of the highest rates of disability of any U.S. racial group (Barnes, Adams, & Powell-Griner, 2005; Hayward & Heron, 1999; John, 2004; John, Hennessy, & Denny, 1999; Waidmann & Liu, 2000). Rates of disability among AI/ANs far exceed those of their non-Hispanic White counterparts. Data from the 1992–1996 Medicare Current Beneficiary Survey indicated that 30% of AI/AN Medicare beneficiaries had one or more limitations in performing an activity of daily living (ADL) compared to 17% of Whites (Waidmann & Liu, 2000). Another analysis based on 1990 Census data noted that mobility limitations, self-care limitations, and work disability were more prevalent among older AI/ANs than non-Hispanic Whites (John, 2004; John et al., 1999). An analysis of the Census 2000 Supplementary Survey found that AI/ANs 45 years or older with functional limitations were older, poorer, less educated, and less likely to be married or employed than those without limitations (Fuller-Thomson & Minkler, 2005). These findings were congruent to those found among older adults in the general U.S. population (Hayward & Heron, 1999; Manton, 1989; Onder et al., 2002). Though provocative, many previous studies have only examined AI/ANs residing in circumscribed geographic regions (Chapleski, Lichtenberg, Dwyer, Youngblade, & Tsai, 1997; Goins, Spencer, Roubideaux, & Manson, 2005; Moss, Roubideaux, Jacobsen, Buchwald, & Manson, 2004) and have lacked comparison groups (Chapleski et al., 1997; Fuller-Thomson & Minkler, 2005). This work highlights the need to better understand the extent of disabilities experienced by older AI/ANs compared to other racial groups and the relationship of disability with sociodemographic characteristics. We, therefore, examined rates of disability among AI/ANs, African Americans, and Whites aged 55 years or older using national data. This study asked three questions: (a) What is the prevalence of disability among older AI/ANs compared with same-age peers of other races? (b) What is the likelihood of having a disability among AI/ANs compared to same-age peers of other races, adjusting for associated sociodemographic characteristics? and (c) What are the sociodemographic correlates of disability among AI/ANs?
Linking parks to people: The key to effective management

Abstract As social institutions, parks have evolved greatly over the past century. Although a view of parks as instruments of sustained development is emerging, there remain strong ties to and beliefs in a conception of parks as separate from society. The article explores two aspects that support a view in which the linkages between people and parks are essential to effective park management. First, an understanding of the social and cultural context in which parks are established is necessary. When such understanding is absent, important social objectives for which parks are established, such as nature conservation, may fail. Second, the traditional rational model of park management needs to be supplemented by an understanding of the knowledge possessed by nonmanagers, including recreationists, landowners, and indigenous populations. Both these aspects present challenging opportunities for social science involvement in policy, research, planning, and management.
Improved hydrate equilibrium measurements in ternary gas and black oil systems

Abstract This work shows that hydrate formation in black oil systems can be incorrectly predicted for two major reasons: (1) a large degree of metastability associated with hydrate formation and dissociation and (2) a previously unconsidered effect of water cut on the water activity and hydrocarbon bubble-point. A new experimental technique is introduced to accurately assess the pressure–temperature equilibrium. A third and forth reason for prediction discrepancies, those of accurate oil characterization and hydrate structural change, awaits future assessment.
Parametrization of the 1S0 two nucleon transition matrix

The 1S0 two-nucleon transition matrix T is constructed from the symmetric part σ of its half-shell elements. The on-shell component of σ is given by the phase shift, while a wide class of parametrizations is suggested for the off-shell part. Restrictions on the off-shell part of σ arising from the short range and the proper one-pion-exchange tail of the nucleon-nucleon interaction are investigated. Using σ in the 1S0 and the Reid soft-core potential in the other partial waves, the binding energy per particle in nuclear matter and 16O and the 18O shell-model spectrum are computed. The sensitivity of these nuclear-structure results is tested with respect to (i) smooth off-shell changes in σ, (ii) various assumptions on the high-energy phase shift, (iii) the charge dependence of the phase shift, and (iv) experimental uncertainties in the phase shift.
Simulating correlated count data

In this study we compare two techniques for simulating count-valued random n-vectors Y with specified mean and correlation structure. The first technique is to use a lognormal-Poisson hierarchy (L-P method). A vector of correlated normals Z is generated and transformed to a vector of lognormals X. Then, Y is generated as conditionally independent Poissons with means Xi. The L-P method is simple, fast, and familiar to many researchers. However, the method requires each Yi to be overdispersed (i.e., σ2 > μ), and only low correlations are possible with this method when the variables have small means. We develop a second technique to generate the elements of Y as overlapping sums (OS) of independent Xj’s (OS method). For example, suppose X, X1, and X2 are independent. If Y1 = X + X1 and Y2 = X + X2, then Y1 and Y2 are correlated because they share the common component X. A generalized version of the OS method for simulating n-vectors of two-parameter count-valued distributions is presented. The OS method is shown to address some of the shortcomings of the L-P method. In particular, underdispersed random variables can be simulated, and high correlations are feasible even when the means are small. However, negative correlations cannot be simulated with the OS method, and when n > 3, the OS method is more complicated to implement than the L-P method.
Sparse Riemannian manifold clustering for HARDI segmentation

We address the problem of segmenting high angular resolution diffusion images of the brain into cerebral regions corresponding to distinct white matter fiber bundles. We cast this problem as a manifold clustering problem in which distinct fiber bundles correspond to different submanifolds of the space of orientation distribution functions (ODFs). Our approach integrates tools from sparse representation theory into a graph theoretic segmentation framework. By exploiting the Riemannian properties of the space of ODFs, we learn a sparse representation for the ODF at each voxel and infer the segmentation by applying spectral clustering to a similarity matrix built from these representations. We evaluate the performance of our method via experiments on synthetic, phantom and real data.
Subsurface seepage of seawater across a barrier: A source of water and salt to peripheral salt basins

Many of the great Phanerozoic salt basins share a common paleogeography, in which a deep lake or sea is separated from the ocean by a narrow barrier. Examples include the Aptian evaporites of the South Atlantic rift basins and the Messinian salt deposits of the Mediterranean Sea and the North Caspian depression. Marine transgressions over the barrier have been proposed as the origin for saline conditions in these basins. We test an alternate hypothesis, that subsurface seepage of seawater through the barrier was a significant source of water, influencing both water level and water composition. Our model permits flux of water and salt into and out of the basin via (1) seepage through the barrier; (2) evaporation from the water surface; (3) rainfall and/or rivers; and (4) incorporation into basin sediments. Our investigation focuses on three settings, a modern analog in the Gregory Rift of northern Kenya, the Messinian Mediterranean basin, and the Early Cretaceous Aptian salt basins of the South Atlantic. We test our model through a numerical simulation, applying reasonable values for the dimensions of the barrier, differences in water level, and hydraulic conductivities to calculate flow rates through the barrier. Modeling results indicate that flux of seawater through a barrier to a peripheral basin ranges from the dominant component of lake water to insignificant, depending on the climate, size of the peripheral basin, and hydraulic conductivity of the barrier. The flux of salt is significant over the full range of modeled hydraulic conductivities, producing brines in the peripheral lake and/or sea within 0.5 m.y. in most cases. This demonstrates that seepage through the barrier can account for lithologic and organic geochemical evidence for saline water conditions, and that marine transgressions across the barrier are not necessary to explain the apparent high salinities.